bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitogen-Activated Protein Kinases and NF-κB Are Involved in TNF-α Responses to Group B Streptococci
Authors: Mancuso Giuseppe , Midiri Angelina , Beninati Concetta , Piraino Giovanna , Valenti Andrea , Nicocia Giacomo , Teti Diana , Cook James , Teti Giuseppe 
Published: April 2014

AbstractTNF-α is a mediator of lethality in experimental infections by group B streptococcus (GBS), an important human pathogen. Little is known of signal transduction pathways involved in GBS-induced TNF-α production. Here we investigate the role of mitogen-activated protein kinases (MAPKs) and NF-κB in TNF-α production by human monocytes stimulated with GBS or LPS, used as a positive control. Western blot analysis of cell lysates indicates that extracellular signal-regulated kinase 1/2 (ERK 1/2), p38, and c-Jun N-terminal kinase MAPKs, as well as IκBα, became phosphorylated, and hence activated, in both LPS- and GBS-stimulated monocytes. The kinetics of these phosphorylation events, as well as those of TNF-α production, were delayed by 30–60 min in GBS-stimulated, relative to LPS-stimulated, monocytes. Selective inhibitors of ERK 1/2 (PD98059 or U0126), p38 (SB203580), or NF-κB (caffeic acid phenetyl ester (CAPE)) could all significantly reduce TNF-α production, although none of the inhibitors used alone was able to completely prevent TNF-α release. However, this was completely blocked by combinations of the inhibitors, including PD98059-SB203580, PD98059-CAPE, or SB203580-CAPE combinations, in both LPS- and GBS-stimulated monocytes. In conclusion, our data indicate that the simultaneous activation of multiple pathways, including NF-κB, ERK 1/2, and p38 MAPKs, is required to induce maximal TNF-α production. Accordingly, in septic shock caused by either GBS or Gram-negative bacteria, complete inhibition of TNF-α release may require treatment with drugs or drug combinations capable of inhibiting multiple activation pathways.
Antibodies Highly Effective in SCID Mice During Infection by the Intracellular BacteriumEhrlichia chaffeensisAre of Picomolar Affinity and Exhibit Preferential Epitope and Isotype Utilization
Authors: Li Julia Shu-yi , Chu Frederick , Reilly Andrew , Winslow Gary M. 
Published: April 2014

AbstractAlthough often considered to be ineffective against intracellular bacteria, Abs, in the absence of lymphocytes, have been shown previously to protect SCID mice from lethal infection by the obligate intracellular bacterium Ehrlichia chaffeensis, even when administered well after infection has been established. To identify characteristics of Abs that are critical for host defense during this intracellular infection, a panel of Ehrlichia-specific mAbs was generated and analyzed. Among 100 Abs recovered, 39 recognized an amino-terminal hypervariable region of an outer membrane protein (OMP), demonstrating that the OMPs are both antigenically variable and immunodominant. A subset of 16 representative OMP-specific Abs was further examined to identify characteristics that were essential for in vivo efficacy. The highly effective Abs recognized a linear epitope within the first hypervariable region of OMP-1g. Only IgG were found to be effective, and among the effective IgG, the following hierarchy was observed: IgG2a &gt; IgG3 = IgG2b. The most striking characteristics of the highly effective Abs were their picomolar binding affinities and long binding t1/2. Thus, although epitope recognition and isotype use may contribute to efficacy, high affinity may be a critical characteristic of Abs that can act effectively during this intracellular bacterial infection.
Viral and Bacterial Infections Induce Expression of Multiple NK Cell Receptors in Responding CD8+ T Cells
Authors: McMahon Christopher W. , Zajac Allan J. , Jamieson Amanda M. , Corral Laura , Hammer Gianna E. , Ahmed Rafi , Raulet David H. 
Published: April 2014

AbstractNK cells express several families of receptors that play central roles in target cell recognition. These NK cell receptors are also expressed by certain memory phenotype CD8+ T cells, and in some cases are up-regulated in T cells responding to viral infection. To determine how the profile of NK receptor expression changes in murine CD8+ T cells as they respond to intracellular pathogens, we used class I tetramer reagents to directly examine Ag-specific T cells during lymphocytic choriomeningitis virus and Listeria monocytogenes infections. We found that the majority of pathogen-specific CD8+ T cells initiated expression of the inhibitory CD94/NKG2A heterodimer, the KLRG1 receptor, and a novel murine NK cell marker (10D7); conversely, very few Ag-specific T cells expressed Ly49 family members. The up-regulation of these receptors was independent of IL-15 and persisted long after clearance of the pathogen. The expression of CD94/NKG2A was rapidly initiated in naive CD8+ T cells responding to peptide Ags in vitro and on many of the naive T cells that proliferate when transferred into lymphopenic (Rag-1−/−) hosts. Thus, CD94/NKG2A expression is a common consequence of CD8+ T cell activation. Binding of the CD94/NKG2A receptor by its ligand (Qa-1b) did not significantly inhibit CD8+ T cell effector functions. However, expression of CD94 and NKG2A transgenes partially inhibited early events of T cell activation. These subtle effects suggest that CD94/NKG2A-mediated inhibition of T cells may be limited to particular circumstances or may synergize with other receptors that are similarly up-regulated.
The Importance of IL-1β and TNF-α, and the Noninvolvement of IL-6, in the Development of Monoclonal Antibody-Induced Arthritis
Authors: Kagari Takashi , Doi Hiromi , Shimozato Takaichi 
Published: April 2014

AbstractInjection of anti-type II collagen Ab and LPS induces arthritis in mice. The levels of IL-1β, IL-6, and chemokines (macrophage inflammatory protein (MIP)-1α, MIP-2, and monocyte chemoattractant protein-1) in the hind paws increased with the onset of arthritis and correlated highly with arthritis scores. The level of TNF-α was also elevated, but only transiently. Quantitative real-time PCR analysis revealed increases in cytokine and chemokine mRNA. To elucidate the contribution of inflammatory cytokines and chemokines in arthritis development more directly, recombinant proteins, neutralizing Abs, and knockout mice were used. The injection of rIL-1β or TNF-α, but not IL-6 or chemokines, induced arthritis when mice were i.v. preinjected with anti-type II collagen Ab. However, a single injection of recombinant cytokines or chemokines into the hind paws did not induce swelling. Arthritis development was inhibited by neutralizing Ab against IL-1β, TNF-α, or MIP-1α. In contrast, the inhibitory effect by anti-MIP-2 Ab was partial and, surprisingly, Abs to IL-6 and monocyte chemoattractant protein-1 showed no inhibitory effect. Furthermore, arthritis development in IL-1R−/− mice and TNFR−/− mice was not observed at all, but severe arthritis was developed in IL-6−/− mice. These results suggest that IL-1β and TNF-α play more crucial roles than IL-6 or chemokines in this model. Because arthritis was also developed in SCID mice, the development of arthritis in the Ab-induced mice model is due to a mechanism that does not involve T or B cells.
Apical, But Not Basolateral, Endotoxin Preincubation Protects Alveolar Epithelial Cells Against Hydrogen Peroxide-Induced Loss of Barrier Function: The Role of Nitric Oxide Synthesis
Authors: Rose Frank , Guthmann Bernd , Tenenbaum Tobias , Fink Ludger , Ghofrani Ardeschir , Weissmann Norbert , König Peter , Ermert Leander , Dahlem Gabriele , Haenze Joerg , Kummer Wolfgang , Seeger Werner , Grimminger Friedrich 
Published: April 2014

AbstractThe influence of LPS preincubation on hydrogen peroxide (H2O2)-induced loss of epithelial barrier function was investigated in rat alveolar epithelial type II cells (ATII). Both apical and basolateral H2O2 administration caused a manyfold increase in transepithelial [3H]mannitol passage. Apical but not basolateral preincubation of ATII with LPS did not influence control barrier properties but fully abrogated the H2O2-induced leakage response. The effect of apical LPS was CD14 dependent and was accompanied by a strong up-regulation of NO synthase II mRNA and protein and NO release. Inhibition of NO by NG-monomethyl-l-arginine suppressed the LPS effect, whereas it was reproduced by exogenous application of gaseous NO or NO donor agents. Manipulation of the glutathione homeostasis (buthionine-(S,R)-sulfoximine) and the cGMP pathway (1H-(1,2,4)oxadiazolo[4,3-α]quinoxaline-1-one; zaprinast) did not interfere with the protective effect of LPS. Superoxide (O⨪2) generation by ATII cells was reduced by exogenous NO and LPS preincubation. O⨪2 scavenging with exogenous superoxide dismutase, the intracellular superoxide dismutase analog Mn(III)tetrakis(4-benzoic acid) porphyrin, and the superoxide scavenger nitroblue tetrazolium and, in particular, hydroxyl radical scavenging with hydroxyl radical scavenger 1,3-dimethyl-thiourea inhibited the H2O2-induced epithelial leakage response. In conclusion, apical but not basolateral LPS preincubation of ATII cells provides strong protection against H2O2-induced transepithelial leakage, attributable to an up-regulation of epithelial NO synthesis. It is suggested that the LPS-induced NO formation is effective via interaction with reactive oxygen species, including superoxide and hydroxyl radicals. The polarized epithelial response to LPS may be part of the lung innate immune system, activated by inhaled endotoxin or under conditions of pneumonia.
Leukocyte Infiltration, But Not Neurodegeneration, in the CNS of Transgenic Mice with Astrocyte Production of the CXC Chemokine Ligand 10
Authors: Boztug Kaan , Carson Monica J. , Pham-Mitchell Ngan , Asensio Valérie C. , DeMartino Julie , Campbell Iain L. 
Published: April 2014

AbstractThe CXC chemokine ligand (CXCL)10 is induced locally in the CNS in diverse pathologic states. The impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. These glial fibrillary acidic protein (GF)-CXCL10 transgenic mice spontaneously developed transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal, and ventricular regions of the brain that were composed of, surprisingly, mainly neutrophils and, to a lesser extent, T cells. No other overt pathologic or physical changes were evident. In addition, the cerebral expression of a number of inflammation-related genes (e.g., cytokines) was not significantly altered in the transgenic mice. The extent of leukocyte recruitment to the brain could be enhanced markedly by peripheral immunization of GF-CXCL10 mice with CFA and pertussis toxin. This was paralleled by a modest, transient increase in the expression of some cytokine and chemokine genes. Analysis of the expression of the CXCL10 receptor, CXCR3, by the brain-infiltrating leukocytes from immunized GF-CXCL10 transgenic mice revealed a significant enrichment for CXCR3-positive cells in the CNS compared with spleen. The majority of cells positive for CXCR3 coexpressed CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. Thus, while astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced recruitment of leukocytes to the CNS, this is not associated with activation of a degenerative immune pathology. Finally, the accumulation of neutrophils in the brain of GF-CXCL10 transgenic mice is apparently independent of CXCR3 and involves an unknown mechanism.
Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection
Authors: Haque M. Azizul , Mizobuchi Teruaki , Yasufuku Kazuhiro , Fujisawa Takehiko , Brutkiewicz Randy R. , Zheng Yan , Woods Kena , Smith Gerald N. , Cummings Oscar W. , Heidler Kathleen M. , Blum Janice S. , Wilkes David S. 
Published: April 2014

AbstractWe have reported that lung allograft rejection involves an immune response to a native protein in the lung, type V collagen (col(V)), and that col(V)-induced oral tolerance prevented acute and chronic rejection. In support of these findings col(V) fragments were detected in allografts during rejection, but not in normal lungs. The purpose of the current study was to isolate and characterize col(V)-specific allograft-infiltrating T cells and to determine their contribution to the rejection response in vivo. Two col(V)-specific T cell lines, LT1 and LT3, were isolated from F344 (RT1lv1) rat lung allografts during rejection that occurred after transplantation into WKY (RT1l) recipients. Both cell lines, but not normal lung lymphocytes, proliferated in response to col(V). Neither LT1 nor LT3 proliferated in response to alloantigens. LT1 and LT3 were CD4+CD25− and produced IFN-γ in response to col(V). Compared with normal CD4+ T cells, both cell lines expressed a limited V-β TCR repertoire. Each cell strongly expressed V-β 9 and 16, but differed in expression of other V-βs. Adoptive transfer of each cell line did not induce pathology in lungs of normal WKY rats. In contrast, adoptive transfer of LT1, but not LT3, caused marked peribronchiolar and perivascular inflammation in isograft (WKY) lungs and abrogated col(V)-induced oral tolerance to allograft (F344) lungs. Collectively, these data show that lung allograft rejection involves both allo- and autoimmune responses, and graft destruction that occurs during the rejection response may expose allograft-infiltrating T cells to potentially antigenic epitopes in col(V).
Differential Expression of the IFN-γ-Inducible CXCR3-Binding Chemokines, IFN-Inducible Protein 10, Monokine Induced by IFN, and IFN-Inducible T Cell α Chemoattractant in Human Cardiac Allografts: Association with Cardiac Allograft Vasculopathy and Acute Rejection
Authors: Zhao David Xiao-Ming , Hu Yenya , Miller Geraldine G. , Luster Andrew D. , Mitchell Richard N. , Libby Peter 
Published: April 2014

Abstract
CXCR3 chemokines exert potent biological effects on both immune and vascular cells. The dual targets suggest their important roles in cardiac allograft vasculopathy (CAV) and rejection. Therefore, we investigated expression of IFN-inducible protein 10 (IP-10), IFN-inducible T cell α chemoattractant (I-TAC), monokine induced by IFN (Mig), and their receptor CXCR3 in consecutive endomyocardial biopsies (n = 133) from human cardiac allografts and corresponding normal donor hearts (n = 11) before transplantation. Allografts, but not normal hearts, contained IP-10, Mig, and I-TAC mRNA. Persistent elevation of IP-10 and I-TAC was associated with CAV. Allografts with CAV had an IP-10-GAPDH ratio 3.7 ± 0.8 compared with 0.8 ± 0.2 in those without CAV (p = 0.004). Similarly, I-TAC mRNA levels were persistently elevated in allografts with CAV (6.7 ± 1.9 in allografts with vs 1.5 ± 0.3 in those without CAV, p = 0.01). In contrast, Mig mRNA was induced only during rejection (2.4 ± 0.9 with vs 0.6 ± 0.2 without rejection, p = 0.015). In addition, IP-10 mRNA increased above baseline during rejection (4.1 ± 2.3 in rejecting vs 1.8 ± 1.2 in nonrejecting biopsies, p = 0.038). I-TAC did not defer significantly with rejection. CXCR3 mRNA persistently elevated after cardiac transplantation. Double immunohistochemistry revealed differential cellular distribution of CXCR3 chemokines. Intragraft vascular cells expressed high levels of IP-10 and I-TAC, while Mig localized predominantly in infiltrating macrophages. CXCR3 was localized in vascular and infiltrating cells. CXCR3 chemokines are induced in cardiac allografts and differentially associated with CAV and rejection. Differential cellular distribution of these chemokines in allografts indicates their central roles in multiple pathways involving CAV and rejection. This chemokine pathway may serve as a monitor and target for novel therapies to prevent CAV and rejection.
The Molecular Basis of Complete Complement C4A and C4B Deficiencies in a Systemic Lupus Erythematosus Patient with HomozygousC4AandC4BMutant Genes
Authors: Rupert Kristi L. , Moulds Joann M. , Yang Yan , Arnett Frank C. , Warren Robert W. , Reveille John D. , Myones Barry L. , Blanchong Carol A. , Yu C. Yung 
Published: April 2014

AbstractThe disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75–96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.
Muscle Responds to an Antibody Reactive with the Acetylcholine Receptor by Up-Regulating Monocyte Chemoattractant Protein 1: A Chemokine with the Potential to Influence the Severity and Course of Experimental Myasthenia Gravis
Authors: Reyes-Reyna Sara , Stegall Timothy , Krolick Keith A. 
Published: April 2014

AbstractAutoantibodies with reactivity against the postjunctional muscle receptor for acetylcholine receptor are able to interfere with contractile function of skeletal muscles and cause the symptoms of myasthenia gravis (MG) in humans, as well as in experimental animal models of MG. In the study described below using a rat model of MG, it was observed that exposure to acetylcholine receptor-reactive Abs also induced increased levels of chemokine (i.e., monocyte chemoattractant protein 1) production by skeletal muscle cells. This was true of both cultured rat myocytes exposed in vitro and rat muscle exposed in vivo following passive Ab transfer. Increased monocyte chemoattractant protein 1 production may explain the increased trafficking of leukocytes through muscle following Ab transfer described in this and other reports. These observations may also be relevant to the induction of disease symptoms in experimental animal models of MG, since numerous reports from this and other laboratories indicate that the cytokine environment provided by leukocytes trafficking through muscle may play a pivotal role in disease progression.
Epstein-Barr Nuclear Antigen 1-Specific CD4+ Th1 Cells Kill Burkitt’s Lymphoma Cells
Authors: Paludan Casper , Bickham Kara , Nikiforow Sarah , Tsang Ming L. , Goodman Kiera , Hanekom Willem A. , Fonteneau Jean-Francois , Stevanović Stefan , Münz Christian 
Published: April 2014

AbstractThe γ-herpesvirus, EBV, is reliably found in a latent state in endemic Burkitt’s lymphoma. A single EBV gene product, Epstein-Barr nuclear Ag 1 (EBNA1), is expressed at the protein level. Several mechanisms prevent immune recognition of these tumor cells, including a block in EBNA1 presentation to CD8+ killer T cells. Therefore, no EBV-specific immune response has yet been found to target Burkitt’s lymphoma. We now find that EBNA1-specific, Th1 CD4+ cytotoxic T cells recognize Burkitt’s lymphoma lines. CD4+ T cell epitopes of EBNA1 are predominantly found in the C-terminal, episome-binding domain of EBNA1, and ∼0.5% of peripheral blood CD4+ T cells are specific for EBNA1. Therefore, adaptive immunity can be directed against Burkitt’s lymphoma, and perhaps this role for CD4+ Th1 cells extends to other tumors that escape MHC class I presentation.
T Cell Subset Patterns That Predict Resistance to Spontaneous Lymphoma, Mammary Adenocarcinoma, and Fibrosarcoma in Mice
Authors: Miller Richard A. , Chrisp Clarence 
Published: April 2014

Abstract
Aging leads to changes in the proportion of several T cell subsets in peripheral blood, but it is not yet known whether these changes have prognostic significance for late-life diseases. To examine this question, levels of T cell subsets were measured at 8 and 18 mo of age in the peripheral blood of mice of a genetically heterogeneous stock, and the mice were then subsequently evaluated for life span and for cause of death. The results indicate that mice whose T cell subset patterns look like those of old mice tend to die at earlier ages, regardless of the specific cause of death. At 18 mo, 39% of the variance within the set of seven measured subsets could be combined statistically into a single number, whose correlation with individual subsets suggested that it could be interpreted as an index of immunological aging. T cell subset pattern, as represented by this index, was a predictor of life span in mice dying of lymphoma, fibrosarcoma, mammary adenocarcinoma, or of all other causes considered together. Even as early as 8 mo of age, T cell subset patterns are significant predictors of all three forms of cancer, although at this age the association is stronger in mated female mice than in virgin mice. These results support two controversial hypotheses, which are not mutually exclusive: 1) early immune senescence might predispose to early death from cancer and 2) differences in aging rate, as monitored by tests of immune status, might accelerate or decelerate a wide range of late life neoplastic diseases.
Cutting Edge: Oral Type I IFN-τ Promotes a Th2 Bias and Enhances Suppression of Autoimmune Encephalomyelitis by Oral Glatiramer Acetate
Authors: Soos Jeanne M. , Stüve Olaf , Youssef Sawsan , Bravo Manuel , Johnson Howard M. , Weiner Howard L. , Zamvil Scott S. 
Published: April 2014

Abstract
IFN-τ, a novel type I IFN that possesses immunomodulatory properties, lacks toxicity normally associated with other type I IFNs. We examined the effects of oral IFN-τ alone and in combination with oral glatiramer acetate in experimental allergic encephalomyelitis (EAE). By comparison of oral administration of IFN-α, -β, and -τ to myelin basic protein-specific TCR-transgenic mice, we demonstrate these type I IFNs promote secretion of the Th2 cytokine IL-10 with similar efficiency. Whereas IFN-α and -β induced IFN-γ secretion, a Th1 cytokine, IFN-τ did not. Oral IFN-τ alone suppressed EAE. When suboptimal doses were administered orally in combination to wild-type mice, IFN-τ and glatiramer acetate had a synergistic beneficial effect in suppression of EAE. This combination was associated with TGF-β secretion and enhanced IL-10 production. Thus, IFN-τ is a potential candidate for use as a single agent or in combination therapy for multiple sclerosis.