bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Regulation of the Expression of CD95 Ligand, Receptor Activator of Nuclear Factor-κB Ligand (RANKL), TNF-Related Apoptosis-Inducing Ligand (TRAIL), and TNF-α During T Cell Activation
Authors: Wang Ruoxiang , Zhang Liying , Zhang Xiaoren , Moreno Jose , Luo Xunyi , Tondravi Mehrdad , Shi Yufang 
Published: April 2014

Abstract
Members of TNF superfamily are characterized by their ability to inflict apoptosis upon binding to their cognate receptors in a homotrimeric manner. These proteins are expressed on different cell types under various conditions. However, the mechanisms governing the expression of these molecules remain elusive. We have found that the TCR signal can elicit the expression of receptor activator of NF-κB ligand (RANKL), TNF-α, CD95L, and TNF-related apoptosis inducing ligand (TRAIL) in T cell hybridoma A1.1 cells, thus allowing us to examine the expression pattern of these molecules under precisely the same conditions. We have previously reported that CD95L expression requires both protein kinase C (PKC) translocation and Ca2+ mobilization and is inhibited by cyclosporin A, and dexamethasone. We demonstrate now that activation-induced expression of RANKL is mediated by Ca2+ mobilization. PKC activation does not induce RANKL expression nor does it synergize with the Ca2+ signal. Activation-induced RANKL expression is blocked by cyclosporin A, but not by dexamethasone. The expression of TNF, in contrast, is mediated by PKC, but not by Ca2+. TNF-α expression is not inhibited by cyclosporin A, but is sensitive to dexamethasone. A1.1 cells constitutively express TRAIL at low levels. Stimulation with anti-CD3 leads to an initial reduction and subsequent increase in TRAIL expression. TRAIL induction is not inhibited by cyclosporin A, but highly sensitive to dexamethasone. Therefore, expression of the TNF superfamily genes is regulated by distinct signals. Detailed understanding of the regulatory mechanisms could provide crucial information concerning the role of these molecules in the modulation of the immune system.
The Inhibitory Action of Sodium Arsenite on Lipopolysaccharide-Induced Nitric Oxide Production in RAW 267.4 Macrophage Cells: A Role of Raf-1 in Lipopolysaccharide Signaling
Authors: Chakravortty Dipshikha , Kato Yutaka , Sugiyama Tsuyoshi , Koide Naoki , Mu Mya Mya , Yoshida Tomoaki , Yokochi Takashi 
Published: April 2014

Abstract
The effect of sodium arsenite (SA) on LPS-induced NO production in RAW 267.4 murine macrophage cells was studied. SA pretreatment of LPS-stimulated RAW cells resulted in a striking reduction in NO production. No significant difference in LPS binding was observed between RAW cells pretreated with SA and control untreated RAW cells, suggesting that SA might impair the intracellular signal pathway for NO production. SA inhibited LPS-induced NF-κB activation by preventing loss of IκB-α and -β. Furthermore, SA blocked phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2), but not phosphorylation of p38 and c-Jun N-terminal kinase. SA treatment resulted in the disappearance of Raf-1, suggesting that it might cause the inhibition of the Erk1/2 mitogen-activated protein (MAP) kinase pathway. The SA-mediated loss of Raf-1 also abolished LPS-induced NF-κB activation as well as the Erk1/2 pathway. The dominant negative mutant of MAP kinase kinase 1 inhibited both NO production and NF-κB activation in LPS-stimulated RAW cells. Taken together, these results indicate that the inhibitory action of SA on NO production in LPS-stimulated macrophages might be due to abrogation of inducible NO synthase induction, and it might be closely related to inactivation of the NF-κB and Erk1/2 MAP kinase pathways through loss of Raf-1.
Targeting Dipeptidyl Peptidase IV (CD26) Suppresses Autoimmune Encephalomyelitis and Up-Regulates TGF-β1 Secretion In Vivo
Authors: Steinbrecher Andreas , Reinhold Dirk , Quigley Laura , Gado Ameer , Tresser Nancy , Izikson Leonid , Born Ilona , Faust Jürgen , Neubert Klaus , Martin Roland , Ansorge Siegfried , Brocke Stefan 
Published: April 2014

Abstract
CD26 or dipeptidyl peptidase IV (DP IV) is expressed on various cell types, including T cells. Although T cells can receive activating signals via CD26, the physiological role of CD26/DP IV is largely unknown. We used the reversible DP IV inhibitor Lys[Z(NO2)]-pyrrolidide (I40) to dissect the role of DP IV in experimental autoimmune encephalomyelitis (EAE) and to explore the therapeutic potential of DP IV inhibition for autoimmunity. I40 administration in vivo decreased and delayed clinical and neuropathological signs of adoptive transfer EAE. I40 blocked DP IV activity in vivo and increased the secretion of the immunosuppressive cytokine TGF-β1 in spinal cord tissue and plasma during acute EAE. In vitro, while suppressing autoreactive T cell proliferation and TNF-α production, I40 consistently up-regulated TGF-β1 secretion. A neutralizing anti-TGF-β1 Ab blocked the inhibitory effect of I40 on T cell proliferation to myelin Ag. DP IV inhibition in vivo was not generally immunosuppressive, neither eliminating encephalitogenic T cells nor inhibiting T cell priming. These data suggest that DP IV inhibition represents a novel and specific therapeutic approach protecting from autoimmune disease by a mechanism that includes an active TGF-β1-mediated antiinflammatory effect at the site of pathology.
Lipopolysaccharide Binding Protein Potentiates Airway Reactivity in a Murine Model of Allergic Asthma
Authors: Strohmeier Gregg R. , Walsh James H. , Klings Elizabeth S. , Farber Harrison W. , Cruikshank William W. , Center David M. , Fenton Matthew J. 
Published: April 2014

Abstract
The development of allergic asthma is influenced by both genetic and environmental factors. Epidemiologic data often show no clear relationship between the levels of allergen and clinical symptoms. Recent data suggest that bacterial LPS may be a risk factor related to asthma severity. Airborne LPS is typically present at levels that are insufficient to activate alveolar macrophages in the absence of the accessory molecule LPS binding protein (LBP). LBP levels are markedly elevated in bronchoalveolar lavage fluids obtained from asthmatic subjects compared with those in normal controls. We hypothesized that LBP present in the lung could augment the pulmonary inflammation and airway reactivity associated with allergic asthma by sensitizing alveolar macrophages to LPS or other bacterial products and triggering them to release proinflammatory mediators. We compared wild-type (WT) and LBP-deficient mice using a defined Ag immunization and aerosol challenge model of allergic asthma. Immunized LBP-deficient mice did not develop substantial Ag-induced airway reactivity, whereas WT mice developed marked bronchoconstriction following aerosol Ag sensitization and challenge with methacholine. Similarly, production of NO synthase 2 protein and the NO catabolite peroxynitrite was dramatically higher in the lungs of WT mice following challenge compared with that in LBP-deficient mice. Thus, NO production appears to correlate with airway reactivity. In contrast, both mice developed similar pulmonary inflammatory cell infiltrates and elevated mucin production. Thus, LBP appears to participate in the development of Ag-induced airway reactivity and peroxynitrite production, but does not seem to be required for the development of pulmonary inflammation.
The Microenvironment of Human Peyer’s Patches Inhibits the Increase in CD38 Expression Associated with the Germinal Center Reaction
Authors: Guilliano Mark J. , Foxx-Orenstein Amy E. , Lebman Deborah A. 
Published: April 2014

Abstract
Analysis of B cells in the human tonsils identified CD38 expression as a hallmark of germinal center (GC) B cells. However, the signals responsible for the in vivo induction of CD38 have not been determined. The primary site for generation of memory and plasma cells in the gastrointestinal tract is the GCs of Peyer’s patches (PP). PP and intestinal mucosa, but not tonsils or oral mucosa, express mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The ligand for MAdCAM-1, integrin α4β7, is expressed on naive B cells and memory B cells that traffic to the gastrointestinal tract. In this study we determine that, unlike tonsil, human PP GC B cells do not express significant levels of CD38. PP B cells can be induced to express CD38 upon culture with CD40 ligand, anti-B cell receptor, and IFN-γ. However, coculture of tonsil naive B cells with an Ab directed against integrin β7 inhibits IFN-γ-induced CD38 hyperexpression. The absence of CD38 on PP GCs suggests that there are tissue-specific pathways of B cell development that differ between tonsil and PP. The differential expression pattern of MAdCAM-1, together with the observation that ligation of β7 can inhibit the induction of CD38 expression, suggests that ligation of α4β7 in vivo may contribute to a PP-specific GC phenotype.
Signals That Initiate Somatic Hypermutation of B Cells In Vitro
Authors: Bergthorsdottir Sigridur , Gallagher Aoife , Jainandunsing Sandra , Cockayne Debra , Sutton James , Leanderson Tomas , Gray David 
Published: April 2014

Abstract
Somatic hypermutation is initiated as B lymphocytes proliferate in germinal centers. The signals that switch on the mutation process are unknown. We have derived an in vitro system to define signals that will initiate mutation in normal, naive splenic B cells. We find that three signals are required to allow detection of somatic mutation in vitro; these are anti-Ig, anti-CD40, and anti-CD38. If any one of these is omitted, mutation remains off. We show that CD40 is obligatory in vivo, as CD40 knockout mice exhibit no Ag-driven mutation. In contrast, CD38 is not, as CD38 knockout mice mutate normally. We believe that, in vitro, CD38, in combination with other stimuli, drives extensive cell division, allowing the detection of mutated sequences. However, in germinal centers in vivo, proliferative activity is instigated by a different molecule. This is the first demonstration of the initiation of hypermutation in vitro with normal splenic B cells using defined stimuli.
Diverse Repertoire of the MHC Class II-Peptide Complexes Is Required for Presentation of Viral Superantigens
Authors: Golovkina Tatyana V. , Agafonova Yelena , Kazansky Dmitry , Chervonsky Alexander 
Published: April 2014

AbstractAmong other features, peptides affect MHC class II molecules, causing changes in the binding of bacterial superantigens (b-Sag). Whether peptides can alter binding of viral superantigens (v-Sag) to MHC class II was not known. Here we addressed the question of whether mutations limiting the diversity of peptides bound by the MHC class II molecules influenced the presentation of v-Sag and, subsequently, the life cycle of the mouse mammary tumor virus (MMTV). T cells reactive to v-Sag were found in mice lacking DM molecules as well as in AbEp-transgenic mice in which MHC class II binding grooves were predominantly occupied by an invariant chain fragment or Eα52–68 peptide, respectively. APCs from the mutant mice failed to present v-Sag, as determined by the lack of Sag-specific T cell activation, Sag-induced T cell deletion, and by the aborted MMTV infection. In contrast, mice that express I-Ab with a variety of bound peptides presented v-Sag and were susceptible to MMTV infection. Comparison of v-Sag and b-Sag presentation by the same mutant cells suggested that presentation of v-Sag had requirements similar to that for presentation of toxic shock syndrome toxin-1. Thus, MHC class II peptide repertoire is critical for recognition of v-Sag by the T cells and affects the outcome of infection with a retrovirus.
αβTCRs Differ in the Degree of Their Specificity for the Positively Selecting MHC/Peptide Ligand
Authors: Kraj Piotr , Pacholczyk Rafal , Ignatowicz Leszek 
Published: April 2014

Abstract
We have tested the peptide specificity of positive selection using three transgenic αβTCRs, originally selected on class II MHC (Ab) covalently bound with one peptide Eα (52–68) (Ep). The transgenic TCR specific for the cytochrome c-derived (43–58) peptide was selected on Ab bound with different arrays of endogenous peptides or the analogue of Ep covalently bound to Ab, but not on the original AbEp complex. In contrast, transgenic TCRs specific for two different analogues of the Ep peptide and Ab did not mature as CD4+ T cells in various thymic environments, including the AbEpIi− mice. These results show that TCRs can be promiscuous or specific for the selecting MHC/peptide complex, and suggest that in mice described in this study transgenic expression of the TCR changes the original requirements for the positively selecting MHC/peptide complex. Future studies will determine whether the latter phenomenon is general or specific for this system.
T Cell Phenotypes of the Normal Nasal Mucosa: Induction of Th2 Cytokines and CCR3 Expression by IL-4
Authors: Till Stephen J. , Jopling Louise A. , Wachholz Petra A. , Robson Rachel L. , Qin Shixin , Andrew David P. , Wu Lijun , van Neerven Joost , Williams Timothy J. , Durham Stephen R. , Sabroe Ian 
Published: April 2014

AbstractMucosal environments such as that of the nose are points of first contact between the human organism and its environment. At these sites the immune system must be regulated to differentiate between and respond appropriately to pathogens and harmless contaminants. T cell-driven immune responses broadly fall into Th1- or Th2-type phenotypes, with increasing evidence that the recruitment of these T lymphocyte subsets is mediated by selective expression of specific chemokine receptors. We have investigated the immunology of the normal nasal mucosa. We show that nasal T cell lines from normal individuals, expanded by culture in IL-2, show reduced expression of the Th2-type cytokines IL-4 and IL-5 compared with lines derived from the blood of the same subjects. These T cells also show reduced expression of the Th2-selective chemokine receptor, CCR3, but similar levels of CCR4 compared with the blood-derived lines. This apparent suppression of Th2 cytokine and CCR3 expression by nasal T cells was reversed by addition of IL-4 to the culture medium. These data are consistent with the presence of a nasal mucosal microenvironment that suppresses Th2 responses and may represent a protective measure against atopic allergic disease in humans and a favoring of Th1 responses to infectious agents. In contrast, T cell expression of CCR1 was higher in the nose than in the blood regardless of the culture medium cytokine environment in keeping with a role for this receptor in tissue homing or lymphocyte activation.
Direct Analysis of the Dynamics of the Intestinal Mucosa CD8 T Cell Response to Systemic Virus Infection
Authors: Masopust David , Jiang Jiu , Shen Hao , Lefrançois Leo 
Published: April 2014

Abstract
The CD8 T cell response to vesicular stomatitis virus infection was characterized in the spleen and intestinal mucosa using MHC tetramers. Surprisingly, the primary response persisted in the lamina propria long after the splenic response had declined. Furthermore, the response was characterized by a protracted effector phase in which cytolytic activity in the lamina propria, but not in the spleen, was maintained. The appearance of Ag-specific cells in the intestinal mucosa was largely, though not exclusively, a result of β7 integrin-mediated migration. Infection with Listeria monocytogenes or with vaccinia virus also led to sustained mucosal responses. After reinfection of vesicular stomatitis virus-primed mice with a serotypically distinct virus, a sustained recall response was detected in all tissues. In CD40−/− mice, the mucosal, but not the splenic, response was compromised, resulting in diminished mucosal memory. The recall response was CD40 independent and correlated with memory levels, indicating that the mucosal and systemic responses operated independently. These findings illustrated the integrated yet distinct nature of systemic vs mucosal immune responses.
An Incremental Increase in the Complexity of Peptides Bound to Class II MHC Changes the Diversity of Positively Selected αβ TCRs
Authors: Pacholczyk Rafal , Kraj Piotr , Ignatowicz Leszek 
Published: April 2014

Abstract
Positive selection of the normal repertoire of TCRs results from low-avidity interactions with a set of self-peptides bound to the MHC molecules expressed by thymic epithelial cells. The contribution of the individual peptide to positive selection remains a matter of debate. Here, for the first time, we show that two covalent class II MHC-peptide complexes positively select different TCRs expressing a common transgenic TCRβ-chain and endogenous TCRα-chains. Simultaneous expression of both Ab-peptide complexes changed the diversity of positively selected TCRs, indicating an additive and possibly synergistic effect of various peptides in this process.
Lupus-Specific Antiribonucleoprotein B Cell Tolerance in Nonautoimmune Mice Is Maintained by Differentiation to B-1 and Governed by B Cell Receptor Signaling Thresholds
Authors: Qian Ye , Santiago Carlos , Borrero Michelle , Tedder Thomas F. , Clarke Stephen H. 
Published: April 2014

Abstract
Systemic lupus erythematosus is an autoimmune disease characterized by the presence of autoantibodies. One of the unique targets of the immune system in systemic lupus erythematosus is Sm, a ribonucleoprotein present in all cells. To understand the regulation of B cells specific to the Sm Ag in normal mice, we have generated an Ig H chain transgenic mouse (2-12H Tg). 2-12H Tg mice produce B cells specific for the Sm that remain tolerant due to ignorance. We demonstrate here that anti-Sm B cells of 2-12H Tg mice can differentiate into Sm-specific peritoneal B-1 cells that remain tolerant. Differentiation to B-1 and tolerance are governed by the strength of B cell receptor signaling, since manipulations of the B cell receptor coreceptors CD19 and CD22 affect anti-Sm B cell differentiation and autoantibody production. These results suggest a differentiation scheme in which peripheral ignorance to Sm is maintained in mice by the differentiation of anti-Sm B cells to B-1 cells that have increased activation thresholds.
Depletion of CCR5-Expressing Cells with Bispecific Antibodies and Chemokine Toxins: A New Strategy in the Treatment of Chronic Inflammatory Diseases and HIV
Authors: Brühl Hilke , Cihak Josef , Stangassinger Manfred , Schlöndorff Detlef , Mack Matthias 
Published: April 2014

Abstract
The chemokine receptor CCR5 is expressed on the majority of T cells and monocytes in the inflammatory infiltrate of diseases such as rheumatoid arthritis, renal diseases, and multiple sclerosis. In contrast, little expression of CCR5 is found on peripheral blood leukocytes. A specific depletion of CCR5+ cells could therefore be a useful strategy to reduce the cellular infiltrate in chronic inflammations. Moreover, CCR5 is the major coreceptor for M-tropic HIV-1 strains. Depletion of CCR5+ leukocytes may help to eliminate cells latently infected with HIV-1. We designed two constructs that specifically destroy chemokine receptor-positive cells. The first construct, a bispecific Ab, binds simultaneously to CCR5 and CD3. Thereby it redirects CD3+ T cells against CCR5+ target cells. The Ab specifically depletes CCR5+ T cells and monocytes, but is inactive against cells that do not express CCR5. Furthermore, ex vivo the bispecific Ab eliminated &gt;95% of CCR5+ monocytes and T cells from the synovial fluid of patients with arthritis. Also, we designed a fusion protein of the chemokine RANTES and a truncated version of Pseudomonas exotoxin A. The fusion protein binds to CCR5 and down-modulates the receptor from the cell surface. The chemokine toxin completely destroyed CCR5+ Chinese hamster ovary cells at a concentration of 10 nM, whereas no cytotoxic effect was detectable against CCR5− Chinese hamster ovary cells. Both constructs efficiently deplete CCR5-positive cells, appear as useful agents in the treatment of chronic inflammatory diseases, and may help to eradicate HIV-1 by increasing the turnover of latently infected cells.
Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro
Authors: Frank Markus H. , Denton Mark D. , Alexander Stephen I. , Khoury Samia J. , Sayegh Mohamed H. , Briscoe David M. 
Published: April 2014

Abstract
MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1–10 μM) and the MDR1 P-gp-specific mAb Hyb-241 (1–20 μg/ml), which detected surface P-gp on 21% of human CD3+ T cells and 84% of CD14+ APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40–90% (p &lt; 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with &gt;85% inhibition (p &lt; 0.01) of IL-2, IFN-γ, and TNF-α production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1–10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4+ T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4+ T cellular IFN-γ secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4+ T cells and CD14+ APCs, and that P-gp blockade may attenuate both IFN-γ and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.
A Novel Role of Complement: Mice Deficient in the Fifth Component of Complement (C5) Exhibit Impaired Liver Regeneration
Authors: Mastellos Dimitrios , Papadimitriou John C. , Franchini Silvia , Tsonis Panagiotis A. , Lambris John D. 
Published: April 2014

Abstract
Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl4-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl4. In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2′-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.