bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Self MHC Class II β-Chain Peptide Prevents Diabetes in Nonobese Diabetic Mice
Authors: Chaturvedi Pratibha , Agrawal Babita , Zechel Marc , Lee-Chan Edwin , Singh Bhagirath 
Published: April 2014

AbstractWe explored T cell responses to the self class II MHC (I-Ag7) β-chain-derived peptides in diabetic and prediabetic nonobese diabetic (NOD) mice. We found that one of these immunodominant epitopes of the β-chain of I-Ag7 molecule, peptide 54–76, could regulate autoimmunity leading to diabetes in NOD mice. T cells from prediabetic young NOD mice do not respond to the peptide 54–76, but T cells from diabetic NOD mice proliferated in response to this peptide. T cells from older nondiabetic mice or mice protected from diabetes do not respond to this peptide, suggesting a role for peptide 54–76-specific T cells in pathogenesis of diabetes. We show that this peptide is naturally processed and presented by the NOD APCs to self T cells. However, the peptide-specific T cells generated after immunization of young mice regulate autoimmunity in NOD mice by blocking the diabetogenic cells in adoptive transfer experiments. The NOD mice immunized with this peptide are protected from both spontaneous and cyclophosphamide-induced insulin-dependent diabetes mellitus. Immunization of young NOD mice with this peptide elicited T cell proliferation and production of Th2-type cytokines. In addition, immunization with this peptide induced peptide-specific Abs of IgG1 isotype that recognized native I-Ag7 molecule on the cell surface and inhibited the T cell proliferative responses. These results suggest that I-Aβg7(54–76) peptide-reactive T cells are involved in the pathogenesis of diabetes. However, immunization with this peptide at young age induces regulatory cells and the peptide-specific Abs that can modulate autoimmunity in NOD mice and prevent spontaneous and induced diabetes.
Up-Regulation of Macrophage Inflammatory Protein-3α/CCL20 and CC Chemokine Receptor 6 in Psoriasis
Authors: Homey Bernhard , Dieu-Nosjean Marie-Caroline , Wiesenborn Andrea , Massacrier Catherine , Pin Jean-Jacques , Oldham Elizabeth , Catron Daniel , Buchanan Matthew E. , Müller Anja , deWaal Malefyt Rene , Deng Glenn , Orozco Rocio , Ruzicka Thomas , Lehmann Percy , Lebecque Serge , Caux Christophe , Zlotnik Albert 
Published: April 2014

AbstractAutoimmunity plays a key role in the immunopathogenesis of psoriasis; however, little is known about the recruitment of pathogenic cells to skin lesions. We report here that the CC chemokine, macrophage inflammatory protein-3α, recently renamed CCL20, and its receptor CCR6 are markedly up-regulated in psoriasis. CCL20-expressing keratinocytes colocalize with skin-infiltrating T cells in lesional psoriatic skin. PBMCs derived from psoriatic patients show significantly increased CCR6 mRNA levels. Moreover, skin-homing CLA+ memory T cells express high levels of surface CCR6. Furthermore, the expression of CCR6 mRNA is 100- to 1000-fold higher on sorted CLA+ memory T cells than other chemokine receptors, including CXCR1, CXCR2, CXCR3, CCR2, CCR3, and CCR5. In vitro, CCL20 attracted skin-homing CLA+ T cells of both normal and psoriatic donors; however, psoriatic lymphocytes responded to lower concentrations of chemokine and showed higher chemotactic responses. Using ELISA as well as real-time quantitative PCR, we show that cultured primary keratinocytes, dermal fibroblasts, and dermal microvascular endothelial and dendritic cells are major sources of CCL20, and that the expression of this chemokine can be induced by proinflammatory mediators such as TNF-α/IL-1β, CD40 ligand, IFN-γ, or IL-17. Taken together, these findings strongly suggest that CCL20/CCR6 may play a role in the recruitment of T cells to lesional psoriatic skin.
Histamine Is a Potent Inducer of IL-18 and IFN-γ in Human Peripheral Blood Mononuclear Cells
Authors: Kohka Hideo , Nishibori Masahiro , Iwagaki Hiromi , Nakaya Naoki , Yoshino Tadashi , Kobashi Kenta , Saeki Kiyomi , Tanaka Noriaki , Akagi Tadaatsu 
Published: April 2014

AbstractHistamine (10−7 to 10−4 M) concentration-dependently stimulated the production of IL-18 and IFN-γ and inhibited the production of IL-2 and IL-10 in human PBMCs. Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of histamine on cytokine production were all antagonized by H2 receptor antagonists ranitidine and famotidine in a concentration-dependent manner, but not by H1 and H3 receptor antagonists. Selective H2 receptor agonists, 4-methylhistamine and dimaprit, mimicked the effects of histamine on five kinds of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 μM, respectively. These findings indicated that histamine caused cytokine responses through the stimulation of H2 receptors. All effects of histamine on cytokine responses were also abolished by the presence of either anti-IL-18 Ab or IL-1β-converting enzyme/caspase-1 inhibitor, indicating that the histamine action is dependent on mature IL-18 secretion and that IL-18 production is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependently stimulated IL-12 and IFN-γ production and inhibited the IL-2 and IL-10 production. IFN-γ production induced by IL-18 was inhibited by anti-IL-12 Ab, showing the marked contrast of the effect of histamine. Thus histamine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18-initiating cytokine cascade without inducing IL-12 production.
Alterations in the Spinal Cord T Cell Repertoire During Relapsing Experimental Autoimmune Encephalomyelitis
Authors: Fritz Robert B. , Wang Xudong , Zhao Ming-Lang 
Published: April 2014

AbstractThe CNS T cell repertoire was analyzed by RT-PCR, spectratyping, and nucleotide sequencing of the amplified products at different times following adoptive transfer of a CD4+, Th1, VB2+ encephalitogenic SJL/J proteolipid protein peptide 139–151-specific T cell clone. The third complementarity-determining region of TCR B chains in the spinal cord was used as an indicator of T cell heterogeneity. Spectratypic analysis revealed that a single peak corresponding to the third complementarity-determining region of the initiating T cell clone predominated during the acute phase. During recovery and relapse the complexity of the spectratype increased. DNA sequence analysis revealed that the donor clone predominated at the acute phase. By the first relapse the donor clone, although represented most frequently, was a minority of the total. Spectratypic analysis of the same samples for several other VB families revealed their presence during acute disease or relapses but, with the exception of VB17, their absence during the recovery stage.
IL-2 Unresponsiveness in Anergic CD4+ T Cells Is Due to Defective Signaling Through the Common γ-Chain of the IL-2 Receptor
Authors: Grundström Susanna , Dohlsten Mikael , Sundstedt Anette 
Published: April 2014

Abstract
Repeated administration of the superantigen staphylococcal enterotoxin A to mice transduces a state of anergy in the CD4+ T cell compartment, characterized by inhibition of IL-2 production and clonal expansion in vivo. In contrast to what has been reported on anergic T cell clones in vitro, culture of in vivo anergized CD4+ T cells in the presence of exogenous IL-2 did not overcome the block in responsiveness. In this study, we demonstrate that CD4+ T cells from mice anergized with staphylococcal enterotoxin A also exhibit a reduced proliferative capacity in response to IL-7 and IL-15, cytokines that share a common γ-chain with the IL-2R. Flow-cytometric analysis revealed only modest changes in the expression of the different IL-2R chains. In a number of experiments, our results also provide evidence that excludes a major role of the IL-2R α-chain in this system. According to these results, the inability of anergic cells to respond to IL-2 is not mainly due to a down-regulation of the high affinity IL-2R, but to a perturbation in intracellular signaling. Our study confirmed that the activation and tyrosine phosphorylation of Janus-associated kinase 3 and STAT5 were considerably weaker after anergy induction. Moreover, anergic CD4+ T cells showed significantly reduced DNA-binding ability to STAT5-specific elements. Taken together, we suggest that the observed IL-2 unresponsiveness in anergic CD4+ T cells could be due to a defect in signaling through the common γ-chain of the IL-2R.
Blocking the Common γ-Chain of Cytokine Receptors Induces T Cell Apoptosis and Long-Term Islet Allograft Survival
Authors: Li Xian Chang , Ima Azine , Li Yongsheng , Zheng Xin Xiao , Malek Thomas R. , Strom Terry B. 
Published: April 2014

AbstractThe common γc-chain is an essential signaling component shared by all known T cell growth factor (TCGF) receptors (i.e., IL-2, IL-4, IL-7, IL-9, and IL-15). In the present study, we have studied the effect of γc-chain blockade on T cell activation and allograft rejection. Treatment of B6AF1 (H-2b/d.k) recipient mice with anti-γc mAbs induced long-term survival of DBA/2 (H-2d) islet allografts (&gt;150 days, n = 8), whereas control Ab-treated mice rejected the islet allografts within 17 days (n = 6). The state of engraftment induced by the anti-γc mAbs was remarkably stable, as recipient mice bearing the primary islet allografts accepted a second DBA/2 islet allograft without further immunosuppression and systemic administration of high doses of IL-2Ig fusion protein failed to provoke rejection. Blocking the γc-chain inhibited T cell proliferation and induced T cell apoptosis by repressing expression of Bcl-2. Our data suggest that one means of inducing T cell apoptosis and stable allograft survival can be achieved via γc-chain blockade.
Protein Tyrosine Phosphatase Activity Is Required for IL-4 Induction of IL-4 Receptor α-Chain
Authors: Huang Hua , Paul William E. 
Published: April 2014

AbstractTo investigate the role of protein tyrosine phosphatases in IL-4Rα-chain expression and signaling, we first established that SHP-1, but not SHP-2, coimmunoprecipitated with anti-IL-4Rα chain Abs in extracts prepared from resting lymphocytes. We further observed that the protein tyrosine phosphatase inhibitors Na3VO4 and pervanadate blocked the striking induction of IL-4Rα-chain expression that is mediated by IL-4. However, Na3VO4 did not diminish IL-4-induced Stat6 phosphorylation nor did it block the IL-4-mediated increase in IL-4Rα-chain mRNA. The striking inhibition in total cellular IL-4Rα-chain and in cell surface IL-4 receptors was associated with an inhibition of biosynthetic labeling of IL-4Rα-chain after a 30- min pulse with [35S] methionine, indicating that reduction of IL-4Rα-chain protein resulted from either a diminished production of the receptor or a rapid degradation, possibly as a result of phosphorylation of the receptor in an early biosynthetic cellular compartment. Control of newly synthesized IL-4Rα-chain protein expression by phosphatase may provide a novel means to regulate IL-4 responsiveness.
Non-CD28 Costimulatory Molecules Present in T Cell Rafts Induce T Cell Costimulation by Enhancing the Association of TCR with Rafts
Authors: Yashiro-Ohtani Yumi , Zhou Xu-Yu , Toyo-oka Kazuhito , Tai Xu-Guang , Park Cheung-Seog , Hamaoka Toshiyuki , Abe Ryo , Miyake Kensuke , Fujiwara Hiromi 
Published: April 2014

Abstract
While CD28 functions as the major T cell costimulatory receptor, a number of other T cell molecules have also been described to induce T cell costimulation. Here, we investigated the mechanisms by which costimulatory molecules other than CD28 contribute to T cell activation. Non-CD28 costimulatory molecules such as CD5, CD9, CD2, and CD44 were present in the detergent-insoluble glycolipid-enriched (DIG) fraction/raft of the T cell surface, which is rich in TCR signaling molecules and generates a TCR signal upon recruitment of the TCR complex. Compared with CD3 ligation, coligation of CD3 and CD5 as an example of DIG-resident costimulatory molecules led to an enhanced association of CD3 and DIG. Such a DIG redistribution markedly up-regulated TCR signaling as observed by ZAP-70/LAT activation and Ca2+ influx. Disruption of DIG structure using an agent capable of altering cholesterol organization potently diminished Ca2+ mobilization induced by the coligation of CD3 and CD5. This was associated with the inhibition of the redistribution of DIG although the association of CD3 and CD5 was not affected. Thus, the DIG-resident costimulatory molecules exert their costimulatory effects by contributing to an enhanced association of TCR/CD3 and DIG.
Phosphatidylinositol 3-Kinase as a Mediator of TNF-Induced NF-κB Activation
Authors: Reddy Shrikanth A. G. , Huang Jianyi H. , Liao Warren S.-L. 
Published: April 2014

Abstract
The activation of transcription factor NF-κB by TNF involves the stimulation of a novel signaling cascade. In this paper we show that phosphatidylinositol 3-kinase (PI 3-kinase) may play a pivotal role in TNF-mediated activation of NF-κB-dependent genes. Consistent with its involvement in TNF signaling, PI 3-kinase activities in HepG2 and U937 cells can be stimulated by TNF in a rapid but transient manner through a mechanism that may involve its association with the insulin receptor substrate-1. A dominant-negative mutant of the p85 regulatory subunit of PI 3-kinase, which is a potent inhibitor of PI 3-kinase signaling, effectively blocked the TNF-induced expression of an NF-κB-dependent reporter gene. Although PI 3-kinase may be required for NF-κB activation, overexpression of its p110 catalytic subunit alone was unable to induce an NF-κB/chloramphenicol acetyltransferase (CAT) reporter gene. However, when TNF was added to p110-overexpressing cells, there was a synergistic activation of the NF-κB/CAT reporter, suggesting that other TNF-inducible signals may cooperate with PI 3-kinase to activate NF-κB. Consistent with its role in NF-κB activation, inhibition of PI 3-kinase activity by wortmannin or LY294002 greatly potentiated TNF-induced apoptosis. This TNF/wortmannin-induced apoptosis was markedly prevented in cells overexpressing Rel A. Taken together, our results indicate that a PI 3-kinase-regulated step in TNF-signaling is critical for the expression of NF-κB-dependent genes.
Identification of a Functional NF-κB Site in the Platelet Endothelial Cell Adhesion Molecule-1 Promoter
Authors: Botella Luisa M. , Puig-Kröger Amaya , Almendro Nuria , Sánchez-Elsner Tilman , Muñoz Eduardo , Corbí Angel , Bernabéu Carmelo 
Published: April 2014

AbstractPlatelet endothelial cell adhesion molecule-1 (PECAM-1) is a type I transmembrane adhesion protein of 130 kDa that belongs to a subgroup of the Ig gene superfamily, characterized by the presence of immunoreceptor tyrosine-based inhibitory motifs. PECAM-1 is expressed in circulating platelets, monocytes, neutrophils, a selective subgroup of T cells, and in endothelial cells, where it is preferentially located at intercellular junctions and participates in leukocyte transmigratory processes. The identification of two consensus NF-κB sites within the PECAM-1 promoter led us to analyze their possible involvement in the PECAM-1 expression regulated by inflammatory stimuli. We found that surface expression and promoter activity of PECAM-1 in myeloid cells are regulated by modulators of NF-κB, including TNF-α, PMA, and pyrrolidine dithiocarbamate. Mobility shifts assays identified a specific NF-κB-binding element at +110/+120, whose mutation abolished the basal promoter activity of PECAM-1 and decreased NF-κB-dependent responses of the PECAM-1 gene promoter. Furthermore, cotransfection experiments with an expression vector encoding the p65 subunit of NF-κB showed transactivation of the PECAM-1 promoter. These results demonstrate that NF-κB can regulate the transcriptional activity of PECAM-1.
Differences Among HIV-1 Variants in Their Ability to Elicit Secretion of TNF-α
Authors: Khanna Kristen V. , Yu Xiao-Fang , Ford David H. , Ratner Lee , Hildreth James K. , Markham Richard B. 
Published: April 2014

AbstractHIV-1 infection of human PBMC has been shown to elicit secretion of several different cytokines. TNF-α secretion induced by this virus has been of particular interest because it has been associated with the development of HIV-1 dementia and because TNF-α increases viral replication by enhancing NF-κB interaction with the viral promoter, the HIV-1 long terminal repeat. Thus, an autocrine pathway is potentially created in which HIV-1 stimulates its own replication. Conflicting reports exist, however, on the ability of HIV-1 to induce TNF-α secretion in vitro or in vivo. Using experimental protocols that controlled for potential bacterial endotoxin-induced TNF-α secretion, the current study demonstrates significant differences in TNF-α-eliciting properties among primary and laboratory obtained HIV-1. The relative TNF-α-inducing ability of different variants is conserved when tested using PBMC from different individuals. Elicitation of TNF-α secretion was not blocked by exposure of cells to zidovudine, indicating that viral integration was not required to induce secretion. Rather, the interaction between the virus and cell surface is critical for TNF-α induction, as Abs against CD4 or CCR5 blocked the induction of TNF-α synthesis by PBMC when added before virus exposure. Furthermore, the ability to induce TNF-α secretion mapped to a region of the HIV-1 env gene that includes the third hypervariable domain. Differences in the ability of different HIV-1 variants to elicit TNF-α may account for individual differences in HIV-1 disease course.
A Bactericidal Monoclonal Antibody Elicits a Change in Its Antigen, OspB of Borrelia burgdorferi, That Can Be Detected by Limited Proteolysis
Authors: Katona Laura I. , Ayalew Sahlu , Coleman James L. , Benach Jorge L. 
Published: April 2014

Abstract
mAb CB2, directed against outer surface protein B (OspB), causes bacteriolysis of Borrelia burgdorferi in the absence of complement. How this happens is unknown. We examined the effect of mAb binding on OspB tertiary structure by using limited proteolysis to probe changes in protein conformation. Truncated OspB (tOspB) that lacked N-terminal lipid was cleaved by four enzymes: trypsin, endoproteinase Arg-C, endoproteinase Asp-N, and endoproteinase Glu-C. CB2 affected the cleavage by trypsin and Arg-C, but not by AspN or Glu-C. None of the enzymes cleaved CB2 under these conditions. Both trypsin and Arg-C cleaved tOspB near the N-terminus; CB2 slowed the rate of cleavage, but did not affect the identity of the sites cleaved. Irrelevant mAb had no effect, indicating that the effect was specific. CB2 was active against tOspB of strain B31, but not against tOspB of strain BEP4, to which it does not bind, suggesting that binding was required to elicit the effect on cleavage. With trypsin, CB2 showed a maximal effect at 8 mol of tOspB to 1 mol of mAb. At this ratio, not enough CB2 was present to bind all the tOspB; therefore, either CB2 shows turnover or CB2 acts by binding tOspB and effecting a change in this tOspB such that it, in turn, propagates the effect in other molecules of tOspB. Regardless of the mechanism, these data show that CB2 elicits a change in tOspB that can be measured by its reduced susceptibility to protease cleavage.
Highly Altered Vβ Repertoire of T Cells Infiltrating Long-Term Rejected Kidney Allografts
Authors: Gagne Katia , Brouard Sophie , Giral Magali , Sebille Fabien , Moreau Anne , Guillet Marina , Bignon Jean-Denis , Imbert Berthe-Marie , Cuturi Maria-Cristina , Soulillou Jean-Paul 
Published: April 2014

AbstractChronic rejection represents a major cause of long-term kidney graft loss. T cells that are predominant in long-term rejected kidney allografts (35 ± 10% of area infiltrate) may thus be instrumental in this phenomenom, which is likely to be dependant on the indirect pathway of allorecognition only. We have analyzed the variations in T cell repertoire usage of the Vβ chain at the complementary determining region 3 (CDR3) level in 18 human kidney grafts lost due to chronic rejection. We observed a strongly biased intragraft TCR Vβ usage for the majority of Vβ families and also a very high percentage (55%) of Vβ families exhibiting common and oligoclonal Vβ-Cβ rearrangements in the grafts of patients with chronic rejection associated with superimposed histologically acute lesions. Furthermore, Vβ8 and Vβ23 families exhibited common and oligoclonal Vβ-Jβ rearrangements in 4 of 18 patients (22%). Several CDR3 amino acid sequences were found for the common and oligoclonal Vβ8-Jβ1.4 rearrangement. Quantitative PCR showed that biased Vβ transcripts were also overexpressed in chronically rejected kidneys with superimposed acute lesions. In contrast, T lymphocytes infiltrating rejected allografts with chronic rejection only showed an unaltered Gaussian-type CDR3 length distribution. This pattern suggests that late graft failure associated with histological lesions restricted to Banff-defined chronic rejection does not involve T cell-mediated injury. Thus, our observation suggests that a limited number of determinants stimulates the recipient immune system in long-term allograft failure. The possibility of a local response against viral or parenchymatous cell-derived determinants is discussed.
Retrovirally Mediated IFN-β Transduction of Macrophages Induces Resistance to HIV, Correlated with Up-Regulation of RANTES Production and Down-Regulation of C-C Chemokine Receptor-5 Expression
Authors: Cremer Isabelle , Vieillard Vincent , De Maeyer Edward 
Published: April 2014

AbstractConstitutive expression of IFN-β by HIV target cells may be an alternative or complementary therapeutic approach for the treatment of AIDS. We show that macrophages derived from CD34+ cells from umbilical cord blood can be efficiently transduced by a retroviral vector carrying the IFN-β coding sequence. This results in resistance to infection by a macrophage-tropic HIV type 1, as shown by the drastic reduction in the HIV DNA copy number per cell and in p24 release. Moreover, IFN-β transduction totally blocked secretion of proinflammatory cytokines after HIV infection. The constitutive IFN-β production also resulted in an increased production of IL-12 and IFN-γ Th1-type cytokines and of the β-chemokines macrophage-inflammatory protein-1α, macrophage-inflammatory protein-1β, and RANTES. RANTES was found to be involved in the HIV resistance observed, and this was correlated with a down-regulation of the CCR-5 HIV entry coreceptor. These results demonstrate the feasibility and the efficacy of such IFN-β-mediated gene therapy. In addition to inhibiting HIV replication, IFN-β transduction could have beneficial immune effects in HIV-infected patients by favoring cellular immune responses.
IL-10 Contributes to the Inhibition of Contact Hypersensitivity in Mice Treated with Photodynamic Therapy
Authors: Simkin Guillermo O. , Tao Jing-Song , Levy Julia G. , Hunt David W. C. 
Published: April 2014

Abstract
We have explored the effect of photodynamic therapy (PDT) with verteporfin on the induction and expression of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene (DNFB) in normal mice and IL-10-deficient mice. Our results indicate that DNFB sensitized mice given PDT with verteporfin and whole body red light irradiation exhibited a significant reduction in CHS compared with control animals. Administration of rIL-12 reversed the effect(s) of PDT as did treatment of mice with anti-IL-10-neutralizing Ab. Knockout mice deficient in IL-10 were found to be resistant to the inhibitory effects of PDT. In vitro proliferative responses using spleen cells from DNFB-sensitized and PDT-treated mice showed a significantly lower response to DNBS as compared with cells from DNFB-sensitized mice or DNFB and PDT-treated IL-10-deficient mice. Finally, naive mice exposed to PDT exhibited an increase in skin IL-10 levels, which peaked between 72 and 120 h post-PDT. Together these data support the role of IL-10 as a key modulator in the inhibition of the CHS response by whole body PDT.