bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of A2B Adenosine Receptor Gene Ablation on Proinflammatory Adenosine Signaling in Mast Cells
Authors: Ryzhov Sergey , Zaynagetdinov Rinat , Goldstein Anna E. , Novitskiy Sergey V. , Dikov Mikhail M. , Blackburn Michael R. , Biaggioni Italo , Feoktistov Igor 
Published: April 2014

Abstract
Pharmacological studies suggest that A2B adenosine receptors mediate proinflammatory effects of adenosine in human mast cells in part by up-regulating production of Th2 cytokines and angiogenic factors. This concept has been recently challenged by the finding that mast cells cultured from bone marrow-derived mast cells (BMMCs) of A2B knockout mice display an enhanced degranulation in response to FcεRI stimulation. This finding was interpreted as evidence of anti-inflammatory functions of A2B receptors and it was suggested that antagonists with inverse agonist activity could promote activation of mast cells. In this report, we demonstrate that genetic ablation of the A2B receptor protein has two distinct effects on BMMCs, one is the previously reported enhancement of Ag-induced degranulation, which is unrelated to adenosine signaling; the other is the loss of adenosine signaling via this receptor subtype that up-regulates IL-13 and vascular endothelial growth factor secretion. Genetic ablation of A2B receptors had no effect on A3 adenosine receptor-dependent potentiation of Ag-induced degranulation in mouse BMMCs, but abrogated A2B adenosine receptor-dependent stimulation of IL-13 and vascular endothelial growth factor secretion. Adenosine receptor antagonists MRS1706 and DPCPX with known inverse agonist activity at the A2B subtype inhibited IL-13 secretion induced by the adenosine analog NECA, but did not mimic the enhanced Ag-induced degranulation observed in A2B knockout BMMCs. Thus, our study confirmed the proinflammatory role of adenosine signaling via A2B receptors and the anti-inflammatory actions of A2B antagonists in mouse BMMCs.
Activation of NF-κB1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival
Authors: Song Jianxun , So Takanori , Croft Michael 
Published: April 2014

Abstract
The costimulatory molecule OX40 (CD134) is required in many instances for effective T cell-mediated immunity, controlling proliferation, and survival of T cells after encountering specific Ag. We previously found that the functional targets of OX40 are survivin and aurora B that regulate proliferation and Bcl-2 antiapoptotic family members that regulate survival. However, the intracellular pathways from OX40 that mediate these effects are unclear. In this study, we show that OX40 signaling can target the canonical NF-κB (NF-κB1) pathway in peripheral Ag-responding CD4 T cells. Phosphorylation of IκBα, nuclear translocation of NF-κB1/p50 and RelA, and NF-κB1 activity, are impaired in OX40-deficient T cells. Retroviral transduction of active IκB kinase that constitutively activates NF-κB1 rescues the poor expansion and survival of OX40-deficient T cells, directly correlating with increased expression and activity of survivin, aurora B, and Bcl-2 family members. Moreover, active IκB kinase expression alone is sufficient to restore the defective expansion and survival of OX40-deficient T cells in vivo when responding to Ag. Thus, OX40 signals regulate T cell number and viability through the NF-κB1 pathway that controls expression and activity of intracellular targets for proliferation and survival.
IL-7/Anti-IL-7 mAb Complexes Restore T Cell Development and Induce Homeostatic T Cell Expansion without Lymphopenia
Authors: Boyman Onur , Ramsey Chris , Kim David M. , Sprent Jonathan , Surh Charles D. 
Published: April 2014

Abstract
IL-7, a member of the common γ-chain family of cytokines, is essential for B and T lymphocyte development and homeostasis of mature T cell subsets. Thus, naive and memory T cells are both dependent on IL-7 for survival and homeostatic proliferation under lymphopenic conditions. In line with prior findings with IL-2, we show in this study that the biological activity of IL-7 in vivo is greatly increased by association with anti-IL-7 mAb. Under in vivo conditions, IL-7/mAb complexes displayed 50- to 100-fold higher activity than free IL-7 and induced massive expansion of pre-B cells. IL-7/mAb complexes also increased thymopoiesis in normal mice and restored thymopoeisis in IL-7-deficient mice. For mature T cells, IL-7/mAb complexes induced marked homeostatic proliferation of both naive and memory CD4+ and CD8+ cell subsets even under normal T cell-replete conditions. Finally, IL-7/mAb complexes were able to enhance the magnitude of the primary response of Ag-specific naive CD8+ cells. The strong stimulatory activity of IL-7/mAb complexes could be useful for treatment of immunodeficiency and cancer.
Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells
Authors: van der Vliet Hans J. J. , Wang Ruojie , Yue Simon C. , Koon Henry B. , Balk Steven P. , Exley Mark A. 
Published: April 2014

Abstract
CD1d-restricted invariant NKT (iNKT) cells play important regulatory roles in various immune responses, including antitumor immune responses. Previous studies have demonstrated quantitative and qualitative defects in iNKT cells of cancer patients, and these defects are clinically relevant as they are associated with poor prognosis. In this study we demonstrate that defects in the iNKT cell population can, at least in part, be attributed to defective interactions between iNKT cells and CD1d-expressing circulating myeloid dendritic cells (mDC), as mDC of patients with advanced melanoma and renal cell cancer reduced the activation and Th1 cytokine production of healthy donor-derived iNKT cells. Interestingly, this reduced activation of iNKT cells was restricted to patients with low circulating iNKT cell numbers and could be reversed by IL-12 and in part by the neutralization of TGF-β, but it was further reduced by the neutralization of IL-10 in vitro. Additional experiments revealed discordant roles for TGF-β and IL-10 on human iNKT cells, because TGF-β suppressed iNKT cell activation and proliferation and IFN-γ production while IL-10 was identified as a cytokine involved in stimulating the activation and expansion of iNKT cells that could subsequently suppress NK cell and T cell responses.
Regulatory CD4+ T Cells Are Crucial for Preventing CD8+ T Cell-Mediated Autoimmunity
Authors: Poitrasson-Rivière Maud , Bienvenu Boris , Le Campion Armelle , Bécourt Chantal , Martin Bruno , Lucas Bruno 
Published: April 2014

Abstract
In vivo studies have shown that regulatory CD4+ T cells regulate conventional CD4+ T cell responses to self- and environmental Ags. However, it remains unclear whether regulatory CD4+ T cells control CD8+ T cell responses to self, directly, or indirectly by decreasing available CD4+ T cell help. We have developed an experimental mouse model in which suppressive and helper T cells cannot mediate their functions. The mouse chimeras generated were not viable and rapidly developed multiple organ autoimmunity. These features were correlated with strong CD8+ T cell activation and accumulation in both lymphoid and nonlymphoid organs. In vivo Ab treatment and secondary transfer experiments demonstrated that regulatory CD4+ T cells play an important direct role in the prevention of peripheral CD8+ T cell-mediated autoimmunity.
Regulatory CD4+CD25+Foxp3+ T Cells Selectively Inhibit the Spontaneous Form of Lymphopenia-Induced Proliferation of Naive T Cells
Authors: Winstead Colleen J. , Fraser Joanne M. , Khoruts Alexander 
Published: April 2014

Abstract
Regulatory CD4+CD25+Foxp3+ T cells play a critical role in controlling autoimmunity and T cell homeostasis. However, their role in regulation of lymphopenia-induced proliferation (LIP), a potential mechanism for generation of autoaggressive T cells, has been poorly defined. Currently, two forms of LIP are recognized: spontaneous and homeostatic. Spontaneous LIP is characterized by fast, burst-like cell-cycle activity, and may allow effector T cell differentiation. Homeostatic LIP is characterized by slow and steady cell cycle activity and is not associated with the acquisition of an effector phenotype. In this study, we demonstrate that CD4+CD25+Foxp3+ T cells suppress the spontaneous, but not homeostatic, LIP of naive CD8 and CD4 T cells. However, selective inhibition of spontaneous LIP does not fully explain the tolerogenic role of Tregs in lymphopenia-associated autoimmunity. We show here that suppression of LIP in the lymphoid tissues is independent of Treg-derived IL-10. However, IL-10-deficient Tregs are partially defective in their ability to prevent colitis caused by adoptive transfer of CD4 T cells into RAG−/− mice. We propose that Tregs may inhibit emergence of effector T cells during the inductive phase of the immune response in the secondary lymphoid tissues by IL-10-independent mechanisms. In contrast, Treg-mediated inhibition of established effector T cells does require IL-10. Both Treg functions appear to be important in control of lymphopenia-associated autoimmunity.
Regulatory Role of B Cells in a Murine Model of Allergic Airway Disease
Authors: Singh Anurag , Carson William F. , Secor Eric R. , Guernsey Linda A. , Flavell Richard A. , Clark Robert B. , Thrall Roger S. , Schramm Craig M. 
Published: April 2014

Abstract
Mice sensitized to OVA and subjected to acute OVA aerosol exposures develop allergic airway disease (AAD). However, chronic continuous Ag exposure results in resolution of AAD and the development of local inhalational tolerance (LIT). Because we have previously observed the persistence of B cells in the bronchoalveolar lavage (BAL) and hilar lymph nodes (HLN) at the resolution stage of this model, we investigated the role of B cells in the modulation of AAD. Although B cell-deficient mice developed LIT, adoptive transfer of HLN B cells from LIT mice to OVA-sensitized recipients resulted in attenuated AAD following subsequent OVA aerosol exposure, as determined by reduced BAL leukocytosis and eosinophilia, decreased tissue inflammation, and absent methacholine hyper-responsiveness. In similar adoptive transfer studies, HLN B cells from AAD mice were without effect. The protection transferred by LIT HLN B cells was Ag specific and was associated with accumulation of Foxp3+ T regulatory cells regionally in BAL and HLN, but not systemically in the spleen. Fluorescent labeling of LIT HLN B cells before adoptive transfer demonstrated that these cells had the capacity to migrate to local inflammatory sites. In vitro assessment demonstrated that the LIT HLN B cells exerted this regulatory effect via TGF-β induced conversion of CD4+CD25− T effector cells into functionally suppressive CD4+CD25+Foxp3+ T regulatory cells. These findings illustrated a novel regulatory role for regional B cells in AAD and suggested a possible contributory role of B cells, along with other cell types, in the establishment of LIT.
Molecular and Immunological Characterization of a Wheat Serine Proteinase Inhibitor as a Novel Allergen in Baker's Asthma
Authors: Constantin Claudia , Quirce Santiago , Grote Monika , Touraev Alisher , Swoboda Ines , Stoecklinger Angelika , Mari Adriano , Thalhamer Josef , Heberle-Bors Erwin , Valenta Rudolf 
Published: April 2014

Abstract
IgE-mediated sensitization to wheat flour belongs to the most frequent causes of occupational asthma. A cDNA library from wheat seeds was constructed and screened with serum IgE from baker's asthma patients. One IgE-reactive phage clone contained a full-length cDNA coding for an allergen with a molecular mass of 9.9 kDa and an isoelectric point of 6. According to sequence analysis it represents a member of the potato inhibitor I family, a group of serine proteinase inhibitors, and thus is the first allergen belonging to the group 6 pathogenesis-related proteins. The recombinant wheat seed proteinase inhibitor was expressed in Escherichia coli and purified to homogeneity. According to circular dichroism analysis, it represented a soluble and folded protein with high thermal stability containing mainly β-sheets, random coils, and an α-helical element. The recombinant allergen showed allergenic activity in basophil histamine release assays and reacted specifically with IgE from 3 of 22 baker's asthma patients, but not with IgE from grass pollen allergic patients or patients suffering from food allergy to wheat. Allergen-specific Abs were raised to localize the allergen by immunogold electron microscopy in the starchy endosperm and the aleuron layer. The allergen is mainly expressed in mature wheat seeds and, despite an ∼50% sequence identity, showed no relevant cross-reactivity with allergens from other plant-derived food sources such as maize, rice, beans, or potatoes. Recombinant wheat serine proteinase inhibitor, when used in combination with other specific allergens, may be useful for the diagnosis and therapy of IgE-mediated baker's asthma.
Anthrax Lethal Toxin Enhances TNF-Induced Endothelial VCAM-1 Expression via an IFN Regulatory Factor-1-Dependent Mechanism
Authors: Warfel Jason M. , D'Agnillo Felice 
Published: April 2014

Abstract
Impaired host defenses and vascular dysfunction are hallmarks of the late, antibiotic-refractory stages of systemic anthrax infection. Anthrax lethal toxin (LT), a key virulence factor of Bacillus anthracis, was previously shown to enhance VCAM-1 expression on primary human endothelial cells suggesting a causative link between dysregulated adhesion molecule expression and the poor immune response and vasculitis associated with anthrax. In this study, we report that LT amplification of TNF-induced VCAM-1 expression is driven transcriptionally by the cooperative activation of NF-κB and IFN regulatory factor-1 (IRF-1). LT enhancement of NF-κB phosphorylation and nuclear translocation correlated temporally with a delayed reaccumulation of IκBα, while increased induction of IRF-1 was linked to STAT1 activation. LT failed to augment TNF-induced ICAM-1 or E-selectin expression, two adhesion molecules regulated by NF-κB, but not IRF-1. These results suggest that LT can differentially modulate NF-κB target genes and highlight the importance of IRF-1 in VCAM-1 enhancement. Altering the activity of key transcription factors involved in host response to infection may be a critical mechanism by which LT contributes to anthrax pathogenesis.
Murine Bactericidal/Permeability-Increasing Protein Inhibits the Endotoxic Activity of Lipopolysaccharide and Gram-Negative Bacteria
Authors: Wittmann Irene , Schönefeld Marc , Aichele Diana , Groer Gerhard , Gessner André , Schnare Markus 
Published: April 2014

Abstract
Recognition of LPS by TLR4 initiates inflammatory responses inducing potent antimicrobial immunity. However, uncontrolled inflammatory responses can be detrimental. To prevent the development of septic shock during an infection with Gram-negative bacteria, the immune system has developed mechanisms to neutralize LPS by specialized proteins. In this study, we report the recombinant expression and functional characterization of the mouse homolog of human bactericidal/permeability-increasing protein (BPI). Purified recombinant mouse BPI was able to neutralize LPS-mediated activation of macrophages and to block LPS-dependent maturation of dendritic cells. Recombinant mouse BPI neutralized the capacity of Gram-negative bacteria to activate immune cells, but did not influence the stimulatory properties of Gram-positive bacteria. Unlike human BPI, mouse BPI failed to kill or inhibit the growth of Pseudomonas aeruginosa. Together, these data demonstrate that murine BPI is a potent LPS-neutralizing protein that may limit innate immune responses during Gram-negative infections.
Administration of a Synthetic TLR4 Agonist Protects Mice from Pneumonic Tularemia
Authors: Lembo Annalisa , Pelletier Mark , Iyer Ravi , Timko Michele , Dudda Jan C. , West T. Eoin , Wilson Christopher B. , Hajjar Adeline M. , Skerrett Shawn J. 
Published: April 2014

Abstract
Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30–60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-γ. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.
Tissue Transglutaminase Activation Modulates Inflammation in Cystic Fibrosis via PPARγ Down-Regulation
Authors: Maiuri Luigi , Luciani Alessandro , Giardino Ida , Raia Valeria , Villella Valeria R. , D'Apolito Maria , Pettoello-Mantovani Massimo , Guido Stefano , Ciacci Carolina , Cimmino Mariano , Cexus Olivier N. , Londei Marco , Quaratino Sonia 
Published: April 2014

AbstractCystic fibrosis (CF), the most common life-threatening inherited disease in Caucasians, is due to mutations in the CF transmembrane conductance regulator (CFTR) gene and is characterized by airways chronic inflammation and pulmonary infections. The inflammatory response is not secondary to the pulmonary infections. Indeed, several studies have shown an increased proinflammatory activity in the CF tissues, regardless of bacterial infections, because inflammation is similarly observed in CFTR-defective cell lines kept in sterile conditions. Despite recent studies that have indicated that CF airway epithelial cells can spontaneously initiate the inflammatory cascade, we still do not have a clear insight of the molecular mechanisms involved in this increased inflammatory response. In this study, to understand these mechanisms, we investigated ex vivo cultures of nasal polyp mucosal explants of CF patients and controls, CFTR-defective IB3-1 bronchial epithelial cells, C38 isogenic CFTR corrected, and 16HBE normal bronchial epithelial cell lines. We have shown that a defective CFTR induces a remarkable up-regulation of tissue transglutaminase (TG2) in both tissues and cell lines. The increased TG2 activity leads to functional sequestration of the anti-inflammatory peroxisome proliferator-activated receptor γ and increase of the classic parameters of inflammation, such as TNF-α, tyrosine phosphorylation, and MAPKs. Specific inhibition of TG2 was able to reinstate normal levels of peroxisome proliferator-activated receptor-γ and dampen down inflammation both in CF tissues and CFTR-defective cells. Our results highlight an unpredicted central role of TG2 in the mechanistic pathway of CF inflammation, also opening a possible new wave of therapies for sufferers of chronic inflammatory diseases.
Factor VIII Hydrolysis Mediated by Anti-Factor VIII Autoantibodies in Acquired Hemophilia
Authors: Wootla Bharath , Dasgupta Suryasarathi , Dimitrov Jordan D. , Bayry Jagadeesh , Lévesque Hervé , Borg Jeanne-Yvonne , Borel-Derlon Annie , Rao Desirazu N. , Friboulet Alain , Kaveri Srinivas V. , Lacroix-Desmazes Sébastien 
Published: April 2014

Abstract
Acquired hemophilia is a rare hemorrhagic disorder caused by the spontaneous appearance of inhibitory autoantibodies directed against endogenous coagulation factor VIII (FVIII). Inhibitory Abs also arise in patients with congenital hemophilia A as alloantibodies directed to therapeutic FVIII. Both autoimmune and alloimmune inhibitors neutralize FVIII by steric hindrance. We have described FVIII-hydrolyzing IgG in 50% of inhibitor-positive patients with severe hemophilia A that inactivate therapeutic FVIII. In this study, we investigated the presence of autoimmune FVIII-hydrolyzing IgG in patients with acquired hemophilia. Pooled IgG from healthy donors demonstrated moderate FVIII-hydrolyzing activity (56 ± 26 μmol/min/mol). Purified IgG from 21 of 45 patients with acquired hemophilia demonstrated FVIII hydrolysis rates (mean 219 ± 94 μmol/min/mol) significantly greater than that of control IgG. Three of four patients followed over the course of the disease had rates of FVIII hydrolysis that co-evolved with inhibitory titers in plasma, suggesting that IgG-mediated FVIII hydrolysis participates, in part, in FVIII inactivation. The present work extends the scope of the diseases associated with FVIII proteolysis and points toward the importance of FVIII as a key target substrate for hydrolytic immunoglobulins. Our data suggest that elevated levels of FVIII-hydrolyzing IgG in acquired hemophilia result from the exacerbation of a physiological catalytic immune response.
Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer
Authors: Sebestyén Zsolt , Schooten Erik , Sals Tamara , Zaldivar Irene , San José Esther , Alarcón Balbino , Bobisse Sara , Rosato Antonio , Szöllősi János , Gratama Jan Willem , Willemsen Ralph A. , Debets Reno 
Published: April 2014

Abstract
TCR gene therapy is adversely affected by newly formed TCRαβ heterodimers comprising exogenous and endogenous TCR chains that dilute expression of transgenic TCRαβ dimers and are potentially self-reactive. We have addressed TCR mispairing by using a modified two-chain TCR that encompasses total human CD3ζ with specificities for three different Ags. Transfer of either TCRα:CD3ζ or β:CD3ζ genes alone does not result in surface expression, whereas transfer of both modified TCR chains results in high surface expression, binding of peptide-MHC complexes and Ag-specific T cell functions. Genetic introduction of TCRαβ:ζ does not compromise surface expression and functions of an endogenous TCRαβ. Flow cytometry fluorescence resonance energy transfer and biochemical analyses demonstrate that TCRαβ:CD3ζ is the first strategy that results in highly preferred pairing between CD3ζ-modified TCRα and β chains as well as absence of TCR mispairing between TCR:CD3ζ and nonmodified TCR chains. Intracellular assembly and surface expression of TCR:CD3ζ chains is independent of endogenous CD3γ, δ, and ε. Taken together, our data support the use of TCRαβ:CD3ζ to prevent TCR mispairing, which may provide an adequate strategy to enhance efficacy and safety of TCR gene transfer.