bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Nociceptin Stimulates Neutrophil Chemotaxis and Recruitment: Inhibition by Aspirin-Triggered-15-Epi-Lipoxin A4
Authors: Serhan Charles N. , Fierro Iolanda M. , Chiang Nan , Pouliot Marc 
Published: April 2014

Abstract
The nociceptin receptor (Noci-R) is a G protein-coupled receptor present in neural tissues and its activation by nociceptin is involved in the processing of pain signals. Here, we report that Noci-R is present and functional on peripheral blood polymorphonuclear leukocytes (PMN). Human PMN express mRNA for Noci-R, its nucleotide sequence determined, and specific binding with [125I]-labeled nociceptin gave an apparent Kd ∼1.5 nM for this PMN opioid receptor. Nociceptin evoked PMN chemotaxis with maximal activity at 100 pM, without intracellular Ca2+ mobilization. When injected in murine air pouches, nociceptin elicited leukocyte infiltration in a concentration-dependent fashion. Nociceptin-stimulated PMN infiltration was inhibited by treating mice with a synthetic analog of the aspirin-triggered lipid mediator 15-epi-lipoxin A4. The present results identify nociceptin as a potent chemoattractant and provide a novel link between the neural and immune systems that are blocked by aspirin-triggered lipid mediators and may be relevant in neurogenic inflammation.
Cutting Edge: Human γδ T Cells Are Activated by Intermediates of the 2-C-methyl-d-erythritol 4-phosphate Pathway of Isoprenoid Biosynthesis
Authors: Altincicek Boran , Moll Jens , Campos Narciso , Foerster Gesine , Beck Ewald , Hoeffler Jean-François , Grosdemange-Billiard Catherine , Rodríguez-Concepción Manuel , Rohmer Michel , Boronat Albert , Eberl Matthias , Jomaa Hassan 
Published: April 2014

Abstract
Activation of Vγ9/Vδ2 T cells by small nonprotein Ags is frequently observed after infection with various viruses, bacteria, and eukaryotic parasites. We suggested earlier that compounds synthesized by the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway of isopentenyl pyrophosphate synthesis are responsible for the Vγ9/Vδ2 T cell reactivity of many pathogens. Using genetically engineered Escherichia coli knockout strains, we now demonstrate that the ability of E. coli extracts to stimulate γδ T cell proliferation is abrogated when genes coding for essential enzymes of the MEP pathway, dxr or gcpE, are disrupted or deleted from the bacterial genome.
Cutting Edge: Critical Role of Inducible Costimulator in Germinal Center Reactions
Authors: Dong Chen , Temann Ulla-Angela , Flavell Richard A. 
Published: April 2014

Abstract
Inducible costimulator (ICOS) is a new member of the CD28/CTLA-4 family that is expressed on activated and germinal center (GC) T cells. Recently, we reported that ICOS-deficient mice exhibited profound defects in T cell activation and effector function. Ab responses in a T-dependent primary reaction and in a murine asthma model were also diminished. In the current study, we investigate the mechanism by which ICOS regulates humoral immunity and examine B cell GC reactions in the absence of ICOS. We found that ICOS−/− mice, when immunized with SRBC, had smaller GCs. Furthermore, IgG1 class switching in the GCs was impaired. Remarkably, GC formation in response to a secondary recall challenge was completely absent in ICOS knockout mice. These data establish a critical role of ICOS in regulation of humoral immunity.
Testing Time-, Ignorance-, and Danger-Based Models of Tolerance
Authors: Anderson Colin C. , Carroll Joseph M. , Gallucci Stefania , Ridge John P. , Cheever Allen W. , Matzinger Polly 
Published: April 2014

Abstract
In this study, we present data showing that tolerance to Ags in the periphery is not determined by the time at which the Ag appears, or by special properties of tissues in newborn mice or newly developing immune systems. We placed male grafts onto immunoincompetent female mice, allowed the grafts to heal for up to 5 mo, and then repopulated the recipients with fetal liver stem cells. We found that the newly arising T cells were neither tolerant nor ignorant of the grafts, but promptly rejected them, though they did not reject female grafts, nor show any signs of autoimmunity. We also found that the H-Y Ag was continuously cross-presented on host APCs, that this presentation was immunogenic, not tolerogenic, and that it depended on the continuous presence of the graft. In searching for the stimulus that might activate the host APCs, we analyzed mRNA expression with a highly sensitive real-time quantitative PCR assay. By using two different “housekeeping” molecules for comparison, we analyzed the message levels for several stress and/or inflammatory molecules in the healed grafts. We found that the long-healed grafts were not equivalent to “normal” skin because the healed grafts expressed lower levels of GAPDH. Altogether, these data suggest that acceptance vs rejection of peripheral tissues is not attributable to ignorance, timing-based tolerance, or special circulation properties of naive T cells in neonatal tissues. It is more likely attributable to an aspect of the context of Ag presentation that remains to be identified.
Functional Caspase-1 Is Required for Langerhans Cell Migration and Optimal Contact Sensitization in Mice
Authors: Antonopoulos Christos , Cumberbatch Marie , Dearman Rebecca J. , Daniel Richard J. , Kimber Ian , Groves Richard W. 
Published: April 2014

Abstract
Langerhans cell (LC) migration from epidermis to draining lymph node is a critical first step in cutaneous immune responses. Both TNF-α and IL-1β are important signals governing this process, but the potential regulatory role of IL-1α processing by caspase-1 is unknown. In wild-type (WT) mice, application of the contact allergens 2,4-dinitrofluorobenzine and oxazolone lead to a marked reduction in epidermal LC numbers, but in caspase-1-deficient mice this reduction was not observed. Moreover, although intradermal injection of TNF-α (50 ng) induced epidermal LC migration in WT mice, this cytokine failed to induce LC migration in caspase-1-deficient mice. Intradermal IL-1β (50 ng) caused a similar reduction in epidermal LC numbers in both WT and caspase-1-deficient mice, indicating that, given an appropriate signal, caspase-1-deficient epidermal LC are capable of migration. Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazolone was inhibited in caspase-1-deficient mice, indicating a functional consequence of the LC migration defect. In organ culture the caspase-1 inhibitor Ac-YVAD-cmk, but not control peptide, potently inhibited the epidermal LC migration that occurs in this system, and reduced spontaneous migration of LC was observed in skin derived from caspase-1-deficient mice. Moreover, Ac-YVAD-cmk applied to BALB/c mouse skin before application of contact sensitizers inhibited LC migration and contact hypersensitivity in vivo. Taken together, these data indicate that caspase-1 may play a central role in the regulation of LC migration and suggest that the activity of this enzyme is amenable to control by specific inhibitors both in vivo and in vitro.
Rapid Peptide Turnover and Inefficient Presentation of Exogenous Antigen Critically Limit the Activation of Self-Reactive CTL by Dendritic Cells
Authors: Ludewig Burkhard , McCoy Kathy , Pericin Marcus , Ochsenbein Adrian F. , Dumrese Tilman , Odermatt Bernhard , Toes Rene E. M. , Melief Cornelis J. M. , Hengartner Hans , Zinkernagel Rolf M. 
Published: April 2014

Abstract
This study evaluated to what extent presentation of exogenously acquired self-Ags via MHC class I molecules on DC might contribute to the activation of self-reactive CTL and subsequent development of autoimmune disease. We show here by using the rat insulin promotor lymphocytic choriomeningitis virus glycoprotein model of autoimmune diabetes that the activation of self-reactive CTL by DC after uptake of exogenous Ag is very limited, first by the short half-life of MHC class I-associated peptides on DC in vitro and in vivo, and second by the rather inefficient MHC class I presentation of cell-associated self-Ags by DC. These two mechanisms are probably crucial in establishing high thresholds for the induction of self-reactive CTL that prevent autoimmune sequelae after release of sequestered and previously immunologically ignored tissue Ags.
A Mucosal IgA-Mediated Excretory Immune System In Vivo
Authors: Robinson Janet K. , Blanchard Thomas G. , Levine Alan D. , Emancipator Steven N. , Lamm Michael E. 
Published: April 2014

AbstractThe capacity of mucosal IgA Abs to serve as an excretory immune system in vivo was investigated. Mice expressing a transgenic TCR were immunized intragastrically with the cognate Ag to elicit a vigorous mucosal IgA Ab response. Soon after i.v. challenge, Ag was detected within the epithelial cells of the small intestinal crypts and to a lesser degree within the epithelial cells higher up the villi, paralleling the gradient in expression of the polymeric Ig receptor and the transport of its ligand, oligomeric IgA. Uptake of Ag into the epithelial cells occurred only from the basolateral aspect and only when Ag complexed to IgA Ab could be present in the lamina propria. The results support the concept that local IgA Abs can excrete Ags from the body by transporting them directly through mucosal epithelial cells, using the same mechanism that transports free IgA into the mucosal secretions.
Translocation of the B Cell Antigen Receptor into Lipid Rafts Reveals a Novel Step in Signaling
Authors: Cheng Paul C. , Brown Bruce K. , Song Wenxia , Pierce Susan K. 
Published: April 2014

Abstract
The cross-linking of the B cell Ag receptor (BCR) leads to the initiation of a signal transduction cascade in which the earliest events involve the phosphorylation of the immunoreceptor tyrosine-based activation motifs of Igα and Igβ by the Src family kinase Lyn and association of the BCR with the actin cytoskeleton. However, the mechanism by which BCR cross-linking initiates the cascade remains obscure. In this study, using various A20-transfected cell lines, biochemical and genetic evidence is provided that BCR cross-linking leads to the translocation of the BCR into cholesterol- and sphingolipid-rich lipid rafts in a process that is independent of the initiation of BCR signaling and does not require the actin cytoskeleton. Translocation of the BCR into lipid rafts did not require the Igα/Igβ signaling complex, was not dependent on engagement of the FcR, and was not blocked by the Src family kinase inhibitor PP2 or the actin-depolymerizing agents cytochalasin D or latrunculin. Thus, cross-linking or oligomerization of the BCR induces the BCR translocation into lipid rafts, defining an event in B cell activation that precedes receptor phosphorylation and association with the actin cytoskeleton.
Compartmentalization of Peyer’s Patch Anlagen Before Lymphocyte Entry
Authors: Hashi Hiroyuki , Yoshida Hisahiro , Honda Kenya , Fraser Stuart , Kubo Hajime , Awane Masaaki , Takabayashi Arimichi , Nakano Hideki , Yamaoka Yoshio , Nishikawa Shin-Ichi 
Published: April 2014

Abstract
We have shown that Peyer’s patch (PP) first develops as a simple and even cell aggregation during embryogenesis. To investigate when and how such a simple cell aggregation forms the complex PP architecture, we analyzed the distribution of cells expressing IL-7Rα (PP inducer cells), VCAM-1 (mesenchymal cells), CD11c (dendritic cells), and mature lymphocytes by whole-mount immunostaining of 17.5 days postcoitus to 2 days postpartum mouse gut. Our results show that compartmentalization of PP anlagen commences at day 18.5 of gestation by clustering and subsequent follicle formation of IL-7Rα+, VCAM-1+, and CD11c+ cells. This process adds the primitive architecture of PP anlage with several follicles in which IL-7Rα+ cells localize in the center, while VCAM-1+ and CD11c+ cells localize at the fringe. This follicle formation is accompanied by the establishment of PP-specific vascular network expressing mucosal addressin cellular adhesion molecule-1. Mature B and T lymphocytes entering in the PP anlage are distributed promptly to their own target zones; B cells to the follicle and T cells to nonfollicular zones. Our analysis of scid/scid mouse indicate that the initial processes including formation of PP-specific vascular network occur in the absence of lymphocytes. These observations indicate that the basic architecture of PP is formed by a set of cell lineages assembled during the initial phase of induction of PP anlagen before entry of mature lymphocytes.
Novel Roles for Lyn in B Cell Migration and Lipopolysaccharide Responsiveness Revealed Using Anti-Double-Stranded DNA Ig Transgenic Mice
Authors: Seo Su-jean , Buckler Jodi , Erikson Jan 
Published: April 2014

Abstract
Lyn-deficient mice produce Abs against dsDNA, yet exhibit exaggerated tolerance to the model Ag hen-egg lysozyme. To investigate this apparent contradiction, and to further examine the function of Lyn in Ag-engaged cells, we have used an anti-dsDNA Ig transgenic model. Previously, looking at these anti-dsDNA B cells in Lyn-sufficient BALB/c mice, we showed that they are regulated by functional inactivation (anergy). In the absence of Lyn, these anti-dsDNA B cells remain unable to secrete Ab. This suggests that functional inactivation of anti-dsDNA B cells does not depend on Lyn, and that the anti-dsDNA Abs that are produced in lyn−/− mice arise from a defect in another mechanism of B cell tolerance. Although the anti-dsDNA B cells remain anergic, Lyn deficiency does restore their ability to proliferate to LPS. This reveals a novel role for Lyn in mediating the LPS unresponsiveness that normally follows surface Ig engagement. Furthermore, Lyn deficiency leads to an altered splenic localization and EBV-induced molecule 1 ligand chemokine responsiveness of anti-dsDNA B cells, as well as an absence of marginal zone B cells, suggesting additional roles for Lyn in controlling the migration and development of specific B cell populations.
Dendritic Cells Acquire Antigens from Live Cells for Cross-Presentation to CTL
Authors: Harshyne Larry A. , Watkins Simon C. , Gambotto Andrea , Barratt-Boyes Simon M. 
Published: April 2014

Abstract
Dendritic cells (DC) can readily capture Ag from dead and dying cells for presentation to MHC class I-restricted CTL. We now show by using a primate model that DC also acquire Ag from healthy cells, including other DC. Coculture assays showed that fluorescently labeled plasma membrane was rapidly and efficiently transferred between DC, and transfer of intracellular proteins was observed to a lesser extent. Acquisition of labeled plasma membrane and intracellular protein was cell contact-dependent and was primarily a function of immature DC, whereas both immature and CD40L-matured DC could serve as donors. Moreover, immature DC could acquire labeled plasma membrane and intracellular proteins from a wide range of hemopoietic cells, including macrophages, B cells, and activated T cells. Notably, macrophages, which readily phagocytose apoptotic bodies, were very inefficient at acquiring labeled plasma membrane and intracellular proteins from other live macrophages or DC. With live-cell imaging techniques, we demonstrate that individual DC physically extract plasma membrane from other DC, generating endocytic vesicles of up to 1 μm in diameter. Finally, DC but not macrophages acquired an endogenous melanoma Ag expressed by live DC and cross-presented Ag to MHC class I-restricted CTL, demonstrating the immunological relevance of our finding. These data show for the first time that DC readily acquire Ag from other live cells. We suggest that Ag acquisition from live cells may provide a novel mechanism whereby DC can present Ag in the absence of direct infection, and may serve to expand and regulate the immune response in vivo.
Concomitant Inhibition of Janus Kinase 3 and Calcineurin-Dependent Signaling Pathways Synergistically Prolongs the Survival of Rat Heart Allografts
Authors: Behbod Fariba , Erwin-Cohen Rebecca A. , Wang Mou-Er , Trawick Barton W. , Qu Xienui , Verani Regina , Kahan Barry D. , Stepkowski Stanislaw M. , Kirken Robert A. 
Published: April 2014

AbstractThe cytoplasmic localized Janus tyrosine kinase 3 (Jak3) is activated by multiple cytokines, including IL-2, IL-4, and IL-7, through engagement of the IL-2R common γ-chain. Genetic inactivation of Jak3 is manifested as SCID in humans and mice. These findings have suggested that Jak3 represents a pharmacological target to control certain lymphoid-derived diseases. Using the rat T cell line Nb2-11c, we document that tyrphostin AG-490 blocked in vitro IL-2-induced cell proliferation (IC50 ∼20 μM), Jak3 autophosphorylation, and activation of its key substrates, Stat5a and Stat5b, as measured by tyrosine/serine phosphorylation analysis and DNA-binding experiments. To test the notion that inhibition of Jak3 provides immunosuppressive potential, a 7-day course of i.v. therapy with 5–20 mg/kg AG-490 was used to inhibit rejection of heterotopically transplanted Lewis (RT1l) heart allografts in ACI (RT1a) recipients. In this study, we report that AG-490 significantly prolonged allograft survival, but also acted synergistically when used in combination with the signal 1 inhibitor cyclosporin A, but not the signal 3 inhibitor, rapamycin. Finally, AG-490 treatment reduced graft infiltration of mononuclear cells and Stat5a/b DNA binding of ex vivo IL-2-stimulated graft infiltrating of mononuclear cells, but failed to affect IL2Rα expression, as judged by RNase protection assays. Thus, inhibition of Jak3 prolongs allograft survival and also potentiates the immunosuppressive effects of cyclosporin A, but not rapamycin.
Normal Cellular Prior Protein Is Preferentially Expressed on Subpopulations of Murine Hemopoietic Cells
Authors: Liu Tong , Li Ruliang , Wong Boon-Seng , Liu Dacai , Pan Tao , Petersen Robert B. , Gambetti Pierluigi , Sy Man-Sun 
Published: April 2014

Abstract
We studied the expression of normal cellular prion protein (PrPC) in mouse lymphoid tissues with newly developed mAbs to PrPC. Most of the mature T and B cells in the peripheral lymphoid organs do not express PrPC. In contrast, most thymocytes are PrPC+. In the bone marrow, erythroid cells and maturing granulocytes are PrPC+. Approximately 50% of the cells in the region of small lymphocytes and progenitor cells also express PrPC. Most of these PrPC+ cells are CD43+, but B220−, surface IgM− (sIgM−), and IL-7R−, a phenotype that belongs to cells not yet committed to the B cell lineage. Another small group of the PrPC+ cell are B220+, and some of these are also sIgM+. The majority of the B220+ cells, however, are PrPC−. Therefore, PrPC is preferentially expressed in early bone marrow progenitor cells and subsets of maturing B cells. Supporting this interpretation is our observation that stimulation of bone marrow cells in vitro with PMA results in a decrease in the number of PrPC+B220− cells with a corresponding increase of sIgM+B220high mature B cells. This result suggests that the PrPC+B220− cells are potential progenitors. Furthermore, in the bone marrow of Rag-1−/− mice, there are an increased number of PrPC+B220− cells, and most of the developmentally arrested pro-B cells in these mice are PrPC+. Collectively, these results suggest that PrPC is expressed preferentially in immature T cells in the thymus and early progenitor cells in the bone marrow, and the expression of PrPC is regulated during hemopoietic differentiation.
Oligodeoxynucleotides Containing CpG Motifs Induce Low Levels of TNF-α in Human B Lymphocytes: Possible Adjuvants for Th1 Responses
Authors: Bohle Barbara , Orel Lukas , Kraft Dietrich , Ebner Christof 
Published: April 2014

Abstract
Oligodeoxynucleotides containing CpG motifs (CpG-ODN) represent potential adjuvants for specific immunotherapy of type I allergies because they foster Th1-like immune responses. However, previous work has shown that CpG-ODN induce systemically active levels of TNF-α in murine macrophages. The goal of the present study was to evaluate the release of TNF-α in human cells by a CpG-ODN proven to induce Th1 immune responses in cells from atopic individuals and in mice. CpG-ODN induced TNF-α in cells from atopic and healthy individuals. However, the amounts were low, as determined by comparison with commonly used Ags. Intracellular cytokine staining of PBMC revealed that CpG-ODN-induced TNF-α derived exclusively from B lymphocytes. TNF-α contributed to the CpG-ODN-augmented proliferation and Ig synthesis in PBMC, but was not involved in IFN-γ synthesis. In conclusion, our findings indicate that certain CpG-ODN induce low amounts of TNF-α in human B lymphocytes and may therefore be used to modulate Th2-biased immune responses in allergic patients.
NK T Cell-Induced Protection Against Diabetes in Vα14-Jα281 Transgenic Nonobese Diabetic Mice Is Associated with a Th2 Shift Circumscribed Regionally to the Islets and Functionally to Islet Autoantigen
Authors: Laloux Véronique , Beaudoin Lucie , Jeske Dirk , Carnaud Claude , Lehuen Agnès 
Published: April 2014

Abstract
The onset of autoimmune diabetes is related to defective immune regulation. Recent studies have shown that NK T cells are deficient in number and function in both diabetic patients and nonobese diabetic (NOD) mice. NK T cells, which are CD1d restricted, express a TCR with an invariant Vα14-Jα281 chain and rapidly produce large amounts of cytokines. Vα14-Jα281 transgenic NOD mice have increased numbers of NK T cells and are protected against diabetes onset. In this study we analyzed where and how NK T cells interfere with the development of the anti-islet autoimmune response. NK T cells, which are usually rare in lymph nodes, are abundant in pancreatic lymph nodes and are also present in islets. IL-4 mRNA levels are increased and IFN-γ mRNA levels decreased in islets from diabetes-free Vα14-Jα281 transgenic NOD mice; the IgG1/IgG2c ratio of autoantibodies against glutamic acid decarboxylase is also increased in these mice. Treatment with IL-12 (a pro-Th1 cytokine) or anti-IL-4 Ab abolishes the diabetes protection in Vα14-Jα281 NOD mice. The protection from diabetes conferred by NK T cells is thus associated with a Th2 shift within islets directed against autoantigen such as glutamic acid decarboxylase. Our findings also demonstrate the key role of IL-4.
Lymphocytes from Autoimmune MRLlpr/lprMice Are Hyperresponsive to IL-18 and Overexpress the IL-18 Receptor Accessory Chain
Authors: Neumann Detlef , Del Giudice Elda , Ciaramella Antonio , Boraschi Diana , Bossù Paola 
Published: April 2014

AbstractMRL lpr/lpr mice spontaneously develop a severe autoimmune lupus syndrome characterized by strong autoantibody production and massive lymphoproliferation, in which IFN-γ plays a major pathogenic effect. The role of the IFN-γ-inducing cytokine IL-18 in the autoimmune syndrome of lpr/lpr mice has been investigated. In response to IL-18, lymph node cells of lpr/lpr mice produce significant amounts of IFN-γ and proliferate more potently as compared with cells from +/+ mice. Cells likely responsible for such hyperresponsiveness to IL-18 include NK cells and the CD4+/CD8+ self-reactive T lymphocytes characteristically present in lymph nodes of lpr/lpr mice. Analysis of the expression of IL-18R complex revealed that mRNA for the IL-18Rα-chain is constitutively expressed at similar level both in +/+ and lpr/lpr lymphocytes. In contrast, the expression of the accessory receptor chain IL-18Rβ is low in unstimulated +/+ cells but significantly high in lpr/lpr cells. Thus, the abnormally high expression of the IL-18R chain IL-18Rβ could be one of the causes of the hyperresponsiveness of lpr/lpr cells to IL-18 at the basis of consequent enhancement of IFN-γ production and development of IFN-γ-dependent autoimmune pathology.