bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Lipopolysaccharide-Binding Protein in Early Alcohol-Induced Liver Injury in Mice
Authors: Uesugi Takehiko , Froh Matthias , Arteel Gavin E. , Bradford Blair U. , Wheeler Michael D. , Gäbele Erwin , Isayama Fuyumi , Thurman Ronald G. 
Published: April 2014

Abstract
Cellular responses to endotoxins are enhanced markedly by LPS-binding protein (LBP). Furthermore, it has been demonstrated that endotoxins and proinflammatory cytokines such as TNF-α participate in early alcohol-induced liver injury. Therefore, in this study, a long-term intragastric ethanol feeding model was used to test the hypothesis that LBP is involved in alcoholic hepatitis by comparing LBP knockout and wild-type mice. Two-month-old female mice were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. There was no difference in mean urine alcohol concentrations between the groups fed ethanol. Dietary alcohol significantly increased liver to body weight ratios and serum alanine aminotransferase levels in wild-type mice (189 ± 31 U/L) over high-fat controls (24 ± 7 U/L), effects which were blunted significantly in LBP knockout mice (60 ± 17 U/L). Although no significant pathological changes were observed in high-fat controls, 4 wk of dietary ethanol caused steatosis, mild inflammation, and focal necrosis in wild-type animals as expected (pathology score, 5.9 ± 0.5). These pathological changes were reduced significantly in LBP knockout mice fed ethanol (score, 2.6 ± 0.5). Endotoxin levels in the portal vein were increased significantly after 4 wk in both groups fed ethanol. Moreover, ethanol increased TNF-α mRNA expression in wild-type, but not in LBP knockout mice. These data are consistent with the hypothesis that LBP plays an important role in early alcohol-induced liver injury by enhancing LPS-induced signal transduction, most likely in Kupffer cells.
The Cutaneous Reverse Arthus Reaction Requires Intercellular Adhesion Molecule 1 and L-Selectin Expression
Authors: Kaburagi Yuko , Hasegawa Minoru , Nagaoka Tetsuya , Shimada Yuka , Hamaguchi Yasuhito , Komura Kazuhiro , Saito Eriko , Yanaba Koichi , Takehara Kazuhiko , Kadono Takafumi , Steeber Douglas A. , Tedder Thomas F. , Sato Shinichi 
Published: April 2014

AbstractThe deposition of immune complexes (IC) induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by expression of multiple adhesion molecules. To assess the role of L-selectin and ICAM-1 in this pathogenetic process, the cutaneous reverse passive Arthus reaction was examined in mice lacking L-selectin (L-selectin−/−), ICAM-1 (ICAM-1−/−), or both (L-selectin/ICAM-1−/−). Edema and hemorrhage, which peaked 4 and 8 h after IC challenge, respectively, were significantly reduced in L-selectin−/−, ICAM-1−/−, and L-selectin/ICAM-1−/− mice compared with wild-type littermates. In general, edema and hemorrhage were more significantly inhibited in ICAM-1−/− mice than in L-selectin−/− mice, but were most significantly reduced in L-selectin/ICAM-1−/− mice compared with ICAM-1−/− or L-selectin−/− mice. Decreased edema and hemorrhage correlated with reduced neutrophil and mast cell infiltration in all adhesion molecule-deficient mice, but leukocyte infiltration was most affected in L-selectin/ICAM-1−/− mice. Reduced neutrophil and mast cell infiltration was also observed for all mutant mice in the peritoneal Arthus reaction. Furthermore, cutaneous TNF-α production was inhibited in each deficient mouse, which paralleled the reductions in cutaneous inflammation. These results indicate that ICAM-1 and L-selectin cooperatively contribute to the cutaneous Arthus reaction by regulating neutrophil and mast cell recruitment and suggest that ICAM-1 and L-selectin are therapeutic targets for human IC-mediated disease.
Lamina Propria CD4+ T Lymphocytes Synergize with Murine Intestinal Epithelial Cells to Enhance Proinflammatory Response Against an Intracellular Pathogen
Authors: Mennechet Franck J. D. , Kasper Lloyd H. , Rachinel Nicolas , Li Wen , Vandewalle Alain , Buzoni-Gatel Dominique 
Published: April 2014

Abstract
Acute and lethal ileitis can be elicited in certain strains of inbred mice after oral infection with the intracellular protozoan parasite Toxoplasma gondii. The development of this inflammatory process is dependent upon the induction of a robust Th1 response, including overproduction of IFN-γ, TNF-α, and NO, as has been reported in other experimental models of human inflammatory bowel disease. In this study we have investigated the role of CD4+ T cells from the lamina propria (LP) in the early inflammatory events after T. gondii infection using isolated and primary cultured intestinal cells from infected mice and immortalized mouse mICcl2 intestinal epithelial cells. Primed LP CD4+ T cells isolated from parasite-infected mice produce substantial quantities of both IFN-γ and TNF-α. IFN-γ- and TNF-α-producing LP CD4+ T cells synergize with infected mICcl2 and enhance the production of several inflammatory chemokines including macrophage-inflammatory protein-2, monocyte chemoattractant protein-1, monocyte chemoattractant protein-3, macrophage-inflammatory protein-1αβ, and IFN-γ-inducible protein-10. Furthermore, primed LP CD4+ T cells cocultured with infected mICcl2 inhibited replication of the parasite in the intestinal epithelial cells. Thus, LP CD4+ T cells can interact with parasite-infected intestinal epithelial cells and alter the expression of several proinflammatory products that have been associated with the development of intestinal inflammation. The interaction between these two components of the gut mucosal compartment (CD4+ T cells and enterocytes) may play a role in the immunopathogenesis of this pathogen-driven experimental inflammatory bowel disease model.
Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification
Authors: Haddad El-Bdaoui , Underwood Stephen L. , Dabrowski Dominika , Birrell Mark A. , McCluskie Kerryn , Battram Cliff H. , Pecoraro Michaela , Foster Martyn L. , Belvisi Maria G. 
Published: April 2014

AbstractIntratracheal instillation of Sephadex particles is a convenient model for assessing the impact of potential anti-inflammatory compounds on lung eosinophilia thought to be a key feature in asthma pathophysiology. However, the underlying cellular and molecular mechanisms involved are poorly understood. We have studied the time course of Sephadex-induced lung eosinophilia, changes in pulmonary T cell numbers, and gene and protein expression as well as the immunological and pharmacological modulation of these inflammatory indices in the Sprague Dawley rat. Sephadex increased T cell numbers (including CD4+ T cells) and evoked a pulmonary eosinophilia that was associated with an increase in gene/protein expression of the Th2-type cytokines IL-4, IL-5, and IL-13 and eotaxin in lung tissue. Sephadex instillation also induced airway hyperreactivity to acetylcholine and bradykinin. A neutralizing Ab (R73) against the αβ-TCR caused 54% depletion of total (CD2+) pulmonary T cells accompanied by a significant inhibition of IL-4, IL-13 and eotaxin gene expression together with suppression (65% inhibition) of eosinophils in lung tissue 24 h after Sephadex treatment. Sephadex-induced eosinophilia and Th2 cytokine gene and/or protein expression were sensitive to cyclosporin A and budesonide, compounds that inhibit T cell function, suggesting a pivotal role for T cells in orchestrating Sephadex-induced inflammation in this model.
α-Actinin Is a Cross-Reactive Renal Target for Pathogenic Anti-DNA Antibodies
Authors: Deocharan Bisram , Qing Xiaoping , Lichauco Juan , Putterman Chaim 
Published: April 2014

Abstract
Anti-DNA Abs commonly found in patients with systemic lupus erythematosus are thought to play an important pathogenic role in lupus nephritis. Anti-DNA Abs may contribute to renal disease by cross-reactivity with renal Ags, the identity of which remain elusive. To identify a target Ag for pathogenic anti-DNA Abs, we performed Western blotting and immunoprecipitations of mesangial cell lysates from the lupus-prone MRL-lpr/lpr mouse and a nonautoimmune BALB/c mouse with the pathogenic anti-DNA Ab R4A. We found that R4A (but not a nonpathogenic Ab mutant of R4A) binds to and immunoprecipitates a 100-kDa protein expressed on the cell surface and in lysates of MRL-lpr/lpr mesangial cells. DNase treatment of the lysate and of the R4A Ab did not effect binding, indicating that the binding of R4A to the 100-kDa protein was direct and not mediated by an antigenic bridge containing DNA. Binding was greatly diminished in BALB/c lysates, suggesting that Ag expression or availability at the level of the target organ may be a factor in determining susceptibility to lupus nephritis. Following identification of this 100-kDa protein as nonmuscle α-actinin, binding of R4A to α-actinin was confirmed by Western blot, ELISA, inhibition studies, and immunofluorescence. High titers of anti-α-actinin Abs were present in sera and kidney eluates of lupus mice with active nephritis. These results indicate that the nephritogenicity of some anti-DNA Abs may be mediated via cross-reactivity with α-actinin. Furthermore, variations in target Ag display between individuals may underlie differential susceptibility to anti-DNA Ab-induced renal disease.
A Novel Approach to the Analysis of Specificity, Clonality, and Frequency of HIV-Specific T Cell Responses Reveals a Potential Mechanism for Control of Viral Escape
Authors: Douek Daniel C. , Betts Michael R. , Brenchley Jason M. , Hill Brenna J. , Ambrozak David R. , Ngai Ka-Leung , Karandikar Nitin J. , Casazza Joseph P. , Koup Richard A. 
Published: April 2014

AbstractEscape from the CD8+ T cell response through epitope mutations can lead to loss of immune control of HIV replication. Theoretically, escape from CD8+ T cell recognition is less likely when multiple TCRs target individual MHC/peptide complexes, thereby increasing the chance that amino acid changes in the epitope could be tolerated. We studied the CD8+ T cell response to six immunodominant epitopes in five HIV-infected subjects using a novel approach combining peptide stimulation, cell surface cytokine capture, flow cytometric sorting, anchored RT-PCR, and real-time quantitative clonotypic TCR tracking. We found marked variability in the number of clonotypes targeting individual epitopes. One subject recognized a single epitope with six clonotypes, most of which were able to recognize and lyse cells expressing a major epitope variant that arose. Additionally, multiple clonotypes remained expanded during the course of infection, irrespective of epitope variant frequency. Thus, CD8+ T cells comprising multiple TCR clonotypes may expand in vivo in response to individual epitopes, and may increase the ability of the response to recognize virus escape mutants.
Cutting Edge: The Minor Histocompatibility Antigen H60 Peptide Interacts with Both H-2Kb and NKG2D
Authors: Cerwenka Adelheid , O’Callaghan Christopher A. , Hamerman Jessica A. , Yadav Rajwardhan , Ajayi Wilfred , Roopenian Derry C. , Joyce Sebastian , Lanier Lewis L. 
Published: April 2014

Abstract
Minor histocompatibility Ags elicit cell-mediated immune responses and graft rejection in individuals receiving MHC-matched tissues. H60 represents a dominant Ag that elicits a strong CTL response in C57BL/6 mice immunized against BALB.B. An 8-aa peptide in the H60 protein is presented by H-2Kb and this is recognized by the TCR as an alloantigen. The intact H60 glycoprotein is a ligand for the costimulatory NKG2D receptor that is expressed by activated CD8+ T cells. Thus, H60 may provide both an allogeneic peptide and its own costimulation. We show that mutation of an H-2Kb-binding anchor residue in the H60 peptide completely abrogates binding of H60 glycoprotein to NKG2D and a synthetic H60 peptide partially blocks the binding of NKG2D to its ligand. Ligands of the human NKG2D receptor are remarkably polymorphic, suggesting that these may also serve as minor histocompatibility Ags.
Cutting Edge: Susceptibility to the Larval Stage of the Helminth ParasiteTaenia crassicepsIs Mediated by Th2 Response Induced Via STAT6 Signaling
Authors: Rodriguez-Sosa Miriam , David John R. , Bojalil Rafael , Satoskar Abhay R. , Terrazas Luis I. 
Published: April 2014

AbstractUsing STAT6−/− BALB/c mice, we analyzed the role of STAT6-induced Th2 response in determining the outcome of murine cysticercosis caused by the helminth parasite Taenia crassiceps. After T. crassiceps infection, wild-type BALB/c mice developed a strong Th2-like response; produced high levels of IgG1, IgE, IL-4, as well as IL-13; and remained susceptible to T. crassiceps. In contrast, similarly infected STAT6−/− mice mounted a strong Th1-like response; produced high levels of IgG2a, IL-12, IFN-γ, as well as nitric oxide; and efficiently controlled T. crassiceps infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to T. crassiceps and, furthermore, that unlike the case in most helminths, immunity against T. crassiceps is mediated by a Th1-like rather than Th2-like response.
IFN-γ-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking
Authors: Dufour Jennifer H. , Dziejman Michelle , Liu Michael T. , Leung Josephine H. , Lane Thomas E. , Luster Andrew D. 
Published: April 2014

AbstractIFN-γ-inducible protein 10 (IP-10, CXCL10), a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is a chemoattractant for activated T cells. Expression of IP-10 is seen in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells into sites of tissue inflammation. To determine the in vivo function of IP-10, we constructed an IP-10-deficient mouse (IP-10−/−) by targeted gene disruption. Immunological analysis revealed that IP-10−/− mice had impaired T cell responses. T cell proliferation to allogeneic and antigenic stimulation and IFN-γ secretion in response to antigenic challenge were impaired in IP-10−/− mice. In addition, IP-10−/− mice exhibited an impaired contact hypersensitivity response, characterized by decreased ear swelling and reduced inflammatory cell infiltrates. T cells recovered from draining lymph nodes also had a decreased proliferative response to Ag restimulation. Furthermore, IP-10−/− mice infected with a neurotropic mouse hepatitis virus had an impaired ability to control viral replication in the brain. This was associated with decreased recruitment of CD4+ and CD8+ lymphocytes into the brain, reduced levels of IFN-γ and the IFN-γ-induced chemokines monokine induced by IFN-γ (Mig, CXCL9) and IFN-inducible T cell α chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of virus-specific IFN-γ-secreting CD8+ cells in the spleen, and reduced levels of demyelination in the CNS. Taken together, our data suggest a role for IP-10 in both effector T cell generation and trafficking in vivo.
Secondary Lymphoid Tissue Chemokine (CCL21) Activates CXCR3 to Trigger a Cl− Current and Chemotaxis in Murine Microglia
Authors: Rappert Angelika , Biber Knut , Nolte Christiane , Lipp Martin , Schubel Andreas , Lu Bao , Gerard Norma P. , Gerard Craig , Boddeke Hendrikus W. G. M. , Kettenmann Helmut 
Published: April 2014

AbstractMicroglial cells represent the major immunocompetent element of the CNS and are activated by any type of brain injury or disease. A candidate for signaling neuronal injury to microglial cells is the CC chemokine ligand CCL21, given that damaged neurons express CCL21. Investigating microglia in acute slices and in culture, we demonstrate that a local application of CCL21 for 30 s triggered a Cl− conductance with lasted for tens of minutes. This response was sensitive to the Cl− channel blockers 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid and 4-acetamide-4′-isothiocyanatostilbene, 2,2′-disulfonic acid. Moreover, CCL21 triggered a chemotaxis response, which was sensitive to Cl− channel blockers. In microglial cells cultured from CCR7 knockout mice, CCL21 produced the same type of Cl− current as well as a chemotaxis response. In contrast, in microglial cells from CXCR3 knockout mice, CCL21 triggered neither a Cl− conductance nor a chemotaxis response after CCL21 application. We conclude that the CCL21-induced Cl− current is a prerequisite for the chemotaxis response mediated by the activation of CXCR3 but not CCR7 receptors, indicating that in brain CCL21 acts via a different receptor system than in lymphoid organs.
TCR Activation of Human T Cells Induces the Production of Exosomes Bearing the TCR/CD3/ζ Complex
Authors: Blanchard Nicolas , Lankar Danielle , Faure Florence , Regnault Armelle , Dumont Céline , Raposo Graça , Hivroz Claire 
Published: April 2014

AbstractWe show in this study that human T cells purified from peripheral blood, T cell clones, and Jurkat T cells release microvesicles in the culture medium. These microvesicles have a diameter of 50–100 nm, are delimited by a lipidic bilayer membrane, and bear TCR β, CD3ε, and ζ. This microvesicle production is regulated because it is highly increased upon TCR activation, whereas another mitogenic signal, such as PMA and ionomycin, does not induce any release. T cell-derived microvesicles also contain the tetraspan protein CD63, suggesting that they originate from endocytic compartments. They contain adhesion molecules such as CD2 and LFA-1, MHC class I and class II, and the chemokine receptor CXCR4. These transmembrane proteins are selectively sorted in microvesicles because CD28 and CD45, which are highly expressed at the plasma membrane, are not found. The presence of phosphorylated ζ in these microvesicles suggests that the CD3/TCR found in the microvesicles come from the pool of complexes that have been activated. Proteins of the transduction machinery, tyrosine kinases of the Src family, and c-Cbl are also observed in the T cell-derived microvesicles. Our data demonstrate that T lymphocytes produce, upon TCR triggering, vesicles whose morphology and phenotype are reminiscent of vesicles of endocytic origin produced by many cell types and called exosomes. Although the exact content of T cell-derived exosomes remains to be determined, we suggest that the presence of TCR/CD3 at their surface makes them powerful vehicles to specifically deliver signals to cells bearing the right combination of peptide/MHC complexes.
Phenotypic and Functional Differences Between NKT Cells Colonizing Splanchnic and Peripheral Lymph Nodes
Authors: Laloux Véronique , Beaudoin Lucie , Ronet Catherine , Lehuen Agnès 
Published: April 2014

AbstractNKT cells are considered unconventional T cells. First, they are restricted by a nonclassical MHC class I molecule, CD1d, which presents glycolipids; second, their TCR repertoire is very limited. After stimulation by their TCR, NKT cells rapidly release large amounts of cytokines, such as IL-4 and IFN-γ. Little is known about NKT cells present in lymph nodes. In the present report we show that NKT cells are differently distributed in various lymph nodes and are, for instance, abundant in pancreatic and mesenteric lymph nodes of C57BL/6 mice and nonobese diabetic mice. The high frequency of NKT cells in splanchnic lymph nodes is not simply a consequence of inflammatory signals, as draining lymph nodes still contain low frequencies of NKT cells after IFA or CFA injections. NKT cells from splanchnic lymph nodes harbor a Vβ repertoire similar to that of splenic and liver NKT cells, in contrast to peripheral NKT cells that are not biased toward Vβ8 segments. Analysis of cytokine production by NKT cells from splanchnic lymph nodes reveals that they produce at least as much IL-4 as IFN-γ, in contrast to NKT cells from other organs (spleen, liver, and peripheral lymph nodes), which produce much more IFN-γ than IL-4. These specific features of NKT cells from splanchnic lymph nodes might explain their protective action against the development of pathogenic Th1 cells in type 1 diabetes.
The Cross-Priming APC Requires a Rel-Dependent Signal to Induce CTL
Authors: Mintern Justine D. , Belz Gabrielle , Gerondakis Steve , Carbone Francis R. , Heath William R. 
Published: April 2014

AbstractInduction of OVA-specific CTL by cross-priming requires help from CD4 T cells, which use CD154 to signal CD40 on the APC. To further dissect the molecular pathways involved in cross-priming, we examined the role of Rel, an NF-κB family member. c-rel−/− mice failed to generate OVA-specific CTL by cross-priming, but could induce CTL to HSV-1. Using chimeric mice, Rel expression was shown to be required by the APC, but not by the T cells. Notably, the deficiency in Rel could be overcome by triggering CD40, implying that the APC required Rel before receipt of the CD40 signal. These data suggest that the cross-priming APC must receive two signals before it can stimulate CTL. The first signal is Rel dependent and is required before activation of CD4 helper T cells, which then deliver the second signal using CD154 to trigger CD40.
Role of TNF Receptor-Associated Factor 2 in the Activation of IgM Secretion by CD40 and CD120b
Authors: Hostager Bruce S. , Bishop Gail A. 
Published: April 2014

AbstractTNFR-associated factors (TRAFs) participate in the signaling of many TNFR family members, including CD40, CD120a (TNFR1), and CD120b (TNFR2). Previously, we found that a dominant-negative TRAF2 molecule inhibits CD40-mediated Ab secretion by the mouse B cell line CH12.LX. However, disruption of the TRAF2 binding site in the cytoplasmic domain of CD40 does not diminish the ability of CD40 to stimulate Ab secretion, nor is this mutation able to circumvent the inhibition of Ab secretion by dominant-negative TRAF2. Here we demonstrate that CD40-induced TNF stimulates IgM production through CD120b and that CD120b signaling is required for optimal CD40-induced IgM secretion. Furthermore, although both CD40 and CD120b can bind TRAF2, TRAF2-dependent CD40 signals cannot substitute for TRAF2-dependent CD120b signals in the activation of IgM secretion. Our results indicate a potentially important role for CD120b in the activation of IgM secretion and that TRAF2 is used by CD40 and CD120b in distinct ways.
Mutational Analysis of Immunoreceptor Tyrosine-Based Inhibition Motifs of the Ig-Like Transcript 2 (CD85j) Leukocyte Receptor
Authors: Bellón Teresa , Kitzig Friederike , Sayós Joan , López-Botet Miguel 
Published: April 2014

AbstractThe inhibitory receptor Ig-like transcript (ILT)2 (leukocyte Ig-like receptor or CD85j) is a type I transmembrane protein expressed by different leukocyte lineages. The extracellular region of ILT2 binds HLA class I molecules, and its cytoplasmic domain displays four immunoreceptor tyrosine-based inhibition motifs. Upon tyrosine phosphorylation ILT2 recruits the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) that is involved in negative signaling. To address the structural basis of ILT2-mediated inhibitory signaling, deletion and single tyrosine mutants were generated and transfected in the COS-7 and rat basophilic leukemia cell lines; their abilities to bind SHP-1 and to inhibit FcεR-induced serotonin release in rat basophilic leukemia cells were studied. Both biochemical and functional analyses revealed tyrosines 644 (SIYATL) and 614 (VTYAQL) as the SHP-1 docking sites required for ILT2 inhibitory function. Substitution of tyrosine 562 (VTYAEV) did not alter receptor function. By contrast, mutation of tyrosine 533 (NLYAAV) interfered with ILT2 tyrosine phosphorylation and the subsequent SHP-1 recruitment, thus supporting a regulatory role for this motif.