bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Profiling Reveals Unique Pathways Associated with Differential Severity of Lyme Arthritis
Authors: Crandall Hillary , Dunn Diane M. , Ma Ying , Wooten R. Mark , Zachary James F. , Weis John H. , Weiss Robert B. , Weis Janis J. 
Published: April 2014

Abstract
The murine model of Lyme disease provides a unique opportunity to study the localized host response to similar stimulus, Borrelia burgdorferi, in the joints of mice destined to develop severe arthritis (C3H) or mild disease (C57BL/6). Pathways associated with the response to infection and the development of Lyme arthritis were identified by global gene expression patterns using oligonucleotide microarrays. A robust induction of IFN-responsive genes was observed in severely arthritic C3H mice at 1 wk of infection, which was absent from mildly arthritic C57BL/6 mice. In contrast, infected C57BL/6 mice displayed a novel expression profile characterized by genes involved in epidermal differentiation and wound repair, which were decreased in the joints of C3H mice. These expression patterns were associated with disease state rather than inherent differences between C3H and C57BL/6 mice, because C57BL/6-IL-10−/− mice infected with B. burgdorferi develop more severe arthritis than C57BL/6 mice and displayed an early gene expression profile similar to C3H mice. Gene expression profiles at 2 and 4 wk postinfection revealed a common response of all strains that was likely to be important for the host defense to B. burgdorferi and mediated by NF-κB-dependent signaling. The gene expression profiles identified in this study add to the current understanding of the host response to B. burgdorferi and identify two novel pathways that may be involved in regulating the severity of Lyme arthritis.
The IFN-Independent Response to Virus Particle Entry Provides a First Line of Antiviral Defense That Is Independent of TLRs and Retinoic Acid-Inducible Gene I
Authors: Paladino Patrick , Cummings Derek T. , Noyce Ryan S. , Mossman Karen L. 
Published: April 2014

Abstract
The innate immune system responds to pathogen infection by eliciting a nonspecific immune response following the recognition of various pathogen-associated molecular patterns. TLRs and the RNA helicases retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 recognize foreign nucleic acid within endosomal and cytoplasmic compartments, respectively, initiating a signaling cascade that involves the induction of type I IFN through the transcription factors IFN regulatory factor (IRF) 3 and NF-κB. However, a recent paradigm has emerged in which bacterial DNA and double-stranded B-form DNA trigger type I IFN production through an uncharacterized TLR- and RIG-I-independent pathway. We have previously described a response in primary fibroblasts wherein the entry of diverse RNA- and DNA-enveloped virus particles is sufficient to induce a subset of IFN-stimulated genes and a complete antiviral response in an IRF3-dependent, IFN-independent manner. In this study, we show that the innate immune response to virus particle entry is independent of both TLR and RIG-I pathways, confirming the existence of novel innate immune mechanisms that result in the activation of IRF3. Furthermore, we propose a model of innate antiviral immunity in which exposure to increasing numbers of virus particles elevates the complexity of the cellular response from an intracellular, IFN-independent response to one involving secretion of cytokines and activation of infiltrating immune cells.
A New Staphylococcal Anti-Inflammatory Protein That Antagonizes the Formyl Peptide Receptor-Like 1
Authors: Prat Cristina , Bestebroer Jovanka , de Haas Carla J. C. , van Strijp Jos A. G. , van Kessel Kok P. M. 
Published: April 2014

Abstract
Bacteria have developed mechanisms to escape the first line of host defense, which is constituted by the recruitment of phagocytes to the sites of bacterial invasion. We previously described the chemotaxis inhibitory protein of Staphylococcus aureus, a protein that blocks the activation of neutrophils via the formyl peptide receptor (FPR) and C5aR. We now describe a new protein from S. aureus that impaired the neutrophil responses to FPR-like1 (FPRL1) agonists. FPRL1 inhibitory protein (FLIPr) inhibited the calcium mobilization in neutrophils stimulated with MMK-1, WKYMVM, prion-protein fragment PrP106–126, and amyloid β1–42. Stimulation with low concentrations of fMLP was partly inhibited. Directed migration was also completely prevented toward MMK-1 and partly toward fMLP. Fluorescence-labeled FLIPr efficiently bound to neutrophils, monocytes, B cells, and NK cells. HEK293 cells transfected with human C5aR, FPR, FPRL1, and FPRL2 clearly showed that FLIPr directly bound to FPRL1 and, at higher concentrations, also to FPR but not to C5aR and FPRL2. FLIPr can reveal unknown inflammatory ligands crucial during S. aureus infections. As a novel described FPRL1 antagonist, it might lead to the development of therapeutic agents in FPRL1-mediated inflammatory components of diseases such as systemic amyloidosis, Alzheimer’s, and prion disease.
Direct CD28 Costimulation Is Required for CD8+ T Cell-Mediated Resistance to an Acute Viral Disease in a Natural Host
Authors: Fang Min , Sigal Luis J. 
Published: April 2014

Abstract
Previous studies have suggested that, differing from model Ags, viruses that replicate extensively in the host still induce normal CD8+ T cell responses in the absence of CD28 costimulation. Because these studies were performed with viruses that do not normally cause acute disease, an important remaining question is whether CD28 costimulation is required for CD8+ T cell-mediated resistance to widely replicating but pathogenic viruses. To address this question, we studied the role of CD28 costimulation in CD8+ T cell-mediated resistance to mousepox, a disease of the mouse caused by the natural mouse pathogen, the ectromelia virus (ECTV). C57BL/6 (B6) mice are naturally resistant to mousepox, partly due to a fast and strong CD8+ T cell response. We found that B6 mice deficient in CD28 (CD28 knockout (KO)) are highly susceptible to lethal mousepox during the early stages of ECTV infection but can be protected by immunization with the antigenically related vaccinia virus (VACV) or by adoptive transfer of CD28 KO anti-VACV memory CD8+ cells. Of interest, a thorough comparison of the CD8+ T cell responses to ECTV and VACV suggests that the main reason for the susceptibility of CD28 KO mice to mousepox is a reduced response at the early stages of infection. Thus, while in the absence of CD28 costimulation the end point strength of the T cell responses to nonpathogenic viruses may appear normal, CD28 costimulation increases the speed of the T cell response and is essential for resistance to a life-threatening acute viral disease.
Recombinant Soluble Forms of Extracellular TLR4 Domain and MD-2 Inhibit Lipopolysaccharide Binding on Cell Surface and Dampen Lipopolysaccharide-Induced Pulmonary Inflammation in Mice
Authors: Mitsuzawa Hiroaki , Nishitani Chiaki , Hyakushima Naoki , Shimizu Takeyuki , Sano Hitomi , Matsushima Norio , Fukase Koichi , Kuroki Yoshio 
Published: April 2014

Abstract
In this study, we sought the possibility of a new therapeutic strategy for dampening endotoxin-induced inflammation using soluble form of extracellular rTLR4 domain (sTLR4) and soluble form of rMD-2 (sMD-2). Addition of sTLR4 plus sMD-2 was significantly effective in inhibiting LPS-elicited IL-8 release from U937 cells and NF-κB activation in the cells transfected with TLR4 and MD-2 when compared with a single treatment with sTLR4 or sMD-2. Thus, we investigated the role of the extracellular TLR4 domain in interaction of lipid A with MD-2. Biotinylated sTLR4 failed to coprecipitate [3H]lipid A when it was sedimented with streptavidin-agarose, demonstrating that the extracellular TLR4 domain does not directly bind lipid A by itself. The amounts of lipid A coprecipitated with sMD-2 significantly increased when coincubated with sTLR4, and sTLR4 increased the affinity of lipid A for the binding to sMD-2. Soluble CD14 is required for the sTLR4-stimulated increase of lipid A binding to sMD-2. We also found that addition of sTLR4 plus sMD-2 inhibited the binding of Alexa-conjugated LPS to the cells expressing TLR4 and MD-2. Murine lungs that had received sTLR4 plus sMD-2 with LPS did not show any findings indicative of interstitial edema, neutrophil flux, and hemorrhage. Coinstillation of sTLR4 plus sMD-2, but not sTLR4 or sMD-2 alone, significantly decreased neutrophil infiltration and TNF-α levels in bronchoalveolar lavage fluids from LPS-treated mice. This study provides novel usage of sTLR4 and sMD-2 as an antagonist against endotoxin-induced pulmonary inflammation.
Plasminogen Activator Inhibitor Type-1-Deficient Mice Have an Enhanced IFN-γ Response to Lipopolysaccharide and Staphylococcal Enterotoxin B
Authors: Renckens Rosemarijn , Pater Jennie M. , Poll Tom van der 
Published: April 2014

Abstract
Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1−/−) mice demonstrated strongly elevated plasma IFN-γ concentrations after injection of either LPS or SEB. In addition, PAI-1−/− splenocytes released more IFN-γ after incubation with LPS or SEB than Wt splenocytes. Both PAI-1−/− CD4+ and CD8+ T cells produced more IFN-γ upon stimulation with SEB. LPS-induced IFN-γ release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN-γ release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN-γ release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.
IRAK-4 Mutation (Q293X): Rapid Detection and Characterization of Defective Post-Transcriptional TLR/IL-1R Responses in Human Myeloid and Non-Myeloid Cells
Authors: Davidson Donald J. , Currie Andrew J. , Bowdish Dawn M. E. , Brown Kelly L. , Rosenberger Carrie M. , Ma Rebecca C. , Bylund Johan , Campsall Paul A. , Puel Anne , Picard Capucine , Casanova Jean-Laurent , Turvey Stuart E. , Hancock Robert E. W. , Devon Rebecca S. , Speert David P. 
Published: April 2014

Abstract
Innate immunodeficiency has recently been reported as resulting from the Q293X IRAK-4 mutation with consequent defective TLR/IL-1R signaling. In this study we report a method for the rapid allele-specific detection of this mutation and demonstrate both cell type specificity and ligand specificity in defective IL-1R-associated kinase (IRAK)-4-deficient cellular responses, indicating differential roles for this protein in human PBMCs and primary dermal fibroblasts and in LPS, IL-1β, and TNF-α signaling. We demonstrate transcriptional and post-transcriptional defects despite NF-κB signaling and intact MyD88-independent signaling and propose that dysfunctional complex 1 (IRAK1/TRAF6/TAK1) signaling, as a consequence of IRAK-4 deficiency, generates specific defects in MAPK activation that could underpin this patient’s innate immunodeficiency. These studies demonstrate the importance of studying primary human cells bearing a clinically relevant mutation; they underscore the complexity of innate immune signaling and illuminate novel roles for IRAK-4 and the fundamental importance of accessory proinflammatory signaling to normal human innate immune responses and immunodeficiencies.
Spontaneous CD8 T Cell Responses against the Melanocyte Differentiation Antigen RAB38/NY-MEL-1 in Melanoma Patients
Authors: Walton Senta M. , Gerlinger Marco , de la Rosa Olga , Nuber Natko , Knights Ashley , Gati Asma , Laumer Monika , Strauss Laura , Exner Carolin , Schäfer Niklaus , Urosevic Mirjana , Dummer Reinhard , Tiercy Jean-Marie , Mackensen Andreas , Jaeger Elke , Lévy Frédéric , Knuth Alexander , Jäger Dirk , Zippelius Alfred 
Published: April 2014

Abstract
The melanocyte differentiation Ag RAB38/NY-MEL-1 was identified by serological expression cloning (SEREX) and is expressed in the vast majority of melanoma lesions. The immunogenicity of RAB38/NY-MEL-1 has been corroborated previously by the frequent occurrence of specific Ab responses in melanoma patients. To elucidate potential CD8 T cell responses, we applied in vitro sensitization with overlapping peptides spanning the RAB38/NY-MEL-1 protein sequence and the reverse immunology approach. The identified peptide RAB38/NY-MEL-150–58 exhibited a marked response in ELISPOT assays after in vitro sensitization of CD8 T cells from HLA-A∗0201+ melanoma patients. In vitro digestion assays using purified proteasomes provided evidence of natural processing of RAB38/NY-MEL-150–58 peptide. Accordingly, monoclonal RAB38/NY-MEL-150–58-specific T cell populations were capable of specifically recognizing HLA-A2+ melanoma cell lines expressing RAB38/NY-MEL-1. Applying fluorescent HLA-A2/RAB38/NY-MEL-150–58 multimeric constructs, we were able to document a spontaneously developed memory/effector CD8 T cell response against this peptide in a melanoma patient. To elucidate the Ag-processing pathway, we demonstrate that RAB38/NY-MEL-150–58 is produced efficiently by the standard proteasome and the immunoproteasome. In addition to the identification of a RAB38/NY-MEL-1-derived immunogenic CD8 T cell epitope, this study is instrumental for both the onset and monitoring of future RAB38/NY-MEL-1-based vaccination trials.
Cutting Edge: TLR2 Is Required for the Innate Response to Porphyromonas gingivalis: Activation Leads to Bacterial Persistence and TLR2 Deficiency Attenuates Induced Alveolar Bone Resorption
Authors: Burns Elia , Bachrach Gilad , Shapira Lior , Nussbaum Gabriel 
Published: April 2014

Abstract
Periodontitis is a chronic inflammatory disease that leads to destruction of the attachment apparatus of the teeth. The presence of particular oral bacteria and the host inflammatory response contribute to disease progression. Porphyromonas gingivalis is a Gram-negative anaerobe considered to be a major periodontal pathogen. Isolated Ags from P. gingivalis activate innate immune cells through TLR2 or TLR4. We challenged TLR2- and TLR4-deficient mice with live P. gingivalis and studied the inflammatory response and bacterial survival. Wild-type and TLR4-deficient mice produced high levels of cytokines in response to P. gingivalis challenge, whereas cytokine levels were nearly absent or delayed in TLR2-deficient mice. Surprisingly, P. gingivalis was cleared far more rapidly in TLR2-deficient mice. In addition, TLR2-deficient mice resisted bone loss following oral infection with P. gingivalis.
Functional Adaptive CD4 Foxp3 T Cells Develop in MHC Class II-Deficient Mice
Authors: Bochtler Petra , Wahl Christian , Schirmbeck Reinhold , Reimann Jörg 
Published: April 2014

AbstractCD4 Foxp3 regulatory T (TR) cells are well-defined regulator T cells known to develop in the thymus through positive selection by medium-to-high affinity TCR-MHC interactions. We asked whether Foxp3 TR cells can be generated in the complete absence of MHC class II molecules. CD4 Foxp3 TR cells are found in secondary lymphoid tissues (spleen and lymph nodes) and peripheral tissues (liver) but not the thymus of severely MHC class II-deficient (Aα−/− B6) mice. These TR cells preferentially express CD103 (but not CD25) but up-regulate CD25 surface expression to high levels in response to TCR-mediated activation. MHC class II-independent Foxp3 TR cells down modulate vaccine-induced, specific antiviral CD8 T cell responses of Aα−/− B6 mice in vivo. Furthermore, these TR cells suppress IL-2 release and proliferative responses in vitro of naive CD25− (CD4 or CD8) T cells from normal B6 mice primed by bead-coupled anti-CD3/anti-CD28 Ab as efficiently as CD4CD25high TR cells from congenic, normal B6 mice. MHC class II-independent CD4 Foxp3+ TR cells thus preferentially express the (TGF-β-induced) integrin molecule αE (CD103), are generated mainly in the periphery and efficiently mediate immunosuppressive effects.
γδ T Cells Promote Anterior Chamber-Associated Immune Deviation and Immune Privilege through Their Production of IL-10
Authors: Ashour Hossam M. , Niederkorn Jerry Y. 
Published: April 2014

Abstract
Anterior chamber-associated immune deviation (ACAID) is a form of peripheral tolerance that is induced by introducing Ags into the anterior chamber (AC) of the eye, and is maintained by Ag-specific regulatory T cells (Tregs). ACAID regulates harmful immune responses that can lead to irreparable injury to innocent bystander cells that are incapable of regeneration. This form of immune privilege in the eye is mediated through Tregs and is a product of complex cellular interactions. These involve F4/80+ ocular APCs, B cells, NKT cells, CD4+CD25+ Tregs, and CD8+ Tregs. γδ T cells are crucial for the generation of ACAID and for corneal allograft survival. However, the functions of γδ T cells in ACAID are unknown. Several hypotheses were proposed for determining the functions of γδ T cells in ACAID. The results indicate that γδ T cells do not cause direct suppression of delayed-type hypersensitivity nor do they act as tolerogenic APCs. In contrast, γδ T cells were shown to secrete IL-10 and facilitate the generation of ACAID Tregs. Moreover, the contribution of γδ T cells ACAID generation could be replaced by adding exogenous recombinant mouse IL-10 to ACAID spleen cell cultures lacking γδ T cells.
Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients
Authors: Battaglia Manuela , Stabilini Angela , Migliavacca Barbara , Horejs-Hoeck Jutta , Kaupper Thomas , Roncarolo Maria-Grazia 
Published: April 2014

Abstract
CD4+CD25+FOXP3+ T regulatory cells (Tregs) are pivotal for the induction and maintenance of peripheral tolerance in both mice and humans. Rapamycin has been shown to promote tolerance in experimental models and to favor CD4+CD25+ Treg-dependent suppression. We recently reported that rapamycin allows in vitro expansion of murine CD4+CD25+FoxP3+ Tregs, which preserve their suppressive function. In the current study, we show that activation of human CD4+ T cells from healthy subjects in the presence of rapamycin leads to growth of CD4+CD25+FOXP3+ Tregs and to selective depletion of CD4+CD25− T effector cells, which are highly sensitive to the antiproliferative effect of the compound. The rapamycin-expanded Tregs suppress proliferation of both syngeneic and allogeneic CD4+ and CD8+ T cells. Interestingly, rapamycin promotes expansion of functional CD4+CD25+FOXP3+ Tregs also in type 1 diabetic patients, in whom a defect in freshly isolated CD4+CD25+ Tregs has been reported. The capacity of rapamycin to allow growth of functional CD4+CD25+FOXP3+ Tregs, but also to deplete T effector cells, can be exploited for the design of novel and safe in vitro protocols for cellular immunotherapy in T cell-mediated diseases.
Dendritic Cell Targeting of Survivin Protein in a Xenogeneic Form Elicits Strong CD4+ T Cell Immunity to Mouse Survivin
Authors: Charalambous Anna , Oks Margarita , Nchinda Godwin , Yamazaki Sayuri , Steinman Ralph M. 
Published: April 2014

Abstract
To determine whether strong CD4+ T cell immunity could be induced to a nonmutated self protein that is important for tumorigenesis, we selectively targeted the xenogeneic form of survivin, a survival protein overexpressed in tumors, to maturing dendritic cells in lymphoid tissues. Dendritic cell targeting via the DEC205 receptor in the presence of anti-CD40 and poly(I:C) as maturation stimuli, induced strong human and mouse survivin-specific CD4+ T cell responses, as determined by IFN-γ, TNF-α, and IL-2 production, as well as the development of lytic MHC class II-restricted T cells and memory. Immunity was enhanced further by depletion of CD25+foxp3+ cells before vaccination. anti-DEC205-human survivin was superior in inducing CD4+ T cell responses relative to other approaches involving survivin plasmid DNA or survivin peptides with adjuvants. However, we were unable to induce CD8+ T cell immunity to survivin by two doses of DEC205-targeted survivin or the other strategies. Therefore, significant CD4+ T cell immunity to a self protein that is overexpressed in most human cancers can be induced by DEC205 targeting of the Ag in its xenogeneic form to maturing DCs.
A Natural Structural Variant of the Mouse TCR β-Chain Displays Intrinsic Receptor Function and Antigen Specificity
Authors: Aublin Anne , Ciofani Maria , Willkomm Nancy , Hamrouni Abdelbasset , Szymczak-Workman Andrea L. , Takahashi Tomio , Sandjeu Yongoua , Guillaume Philippe , Vignali Dario A. A. , Michielin Olivier , Zúñiga-Pflücker Juan Carlos , Maryanski Janet L. 
Published: April 2014

Abstract
The Cβ0 alternate cassette exon is located between the Jβ1 and Cβ1 genes in the mouse TCR β-locus. In T cells with a VDJβ1 rearrangement, the Cβ0 exon may be included in TCRβ transcripts (herein called TCRβ-Cβ0 transcripts), potentially inserting an additional 24 aa between the V and C domains of the TCR β-chain. These TCRβ splice isoforms may be differentially regulated after Ag activation, because we detected TCRβ-Cβ0 transcripts in a high proportion (&gt;60%) of immature and mature T cells having VDJβ1 rearrangements but found a substantially reduced frequency (&lt;35%) of TCRβ-Cβ0 expression among CD8 T cells selected by Ag in vivo. To study the potential activity of the TCRβ-Cβ0 splice variant, we cloned full-length TCR cDNAs by single-cell RT-PCR into retroviral expression vectors. We found that the TCRβ-Cβ0 splice isoform can function during an early stage of T cell development normally dependent on TCR β-chain expression. We also demonstrate that T hybridoma-derived cells expressing a TCRβ-Cβ0 isoform together with the clonally associated TCR α-chain recognize the same cognate peptide-MHC ligand as the corresponding normal αβTCR. This maintenance of receptor function and specificity upon insertion of the Cβ0 peptide cassette signifies a remarkable adaptability for the TCR β-chain, and our findings open the possibility that this splice isoform may function in vivo.