bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Role for the Bactericidal/Permeability Increasing Protein in Interactions of Gram-Negative Bacterial Outer Membrane Blebs with Dendritic Cells
Authors: Schultz Hendrik , Hume Janet , Zhang De Sheng , Gioannini Theresa L. , Weiss Jerrold P. 
Published: April 2014

AbstractThe bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role for BPI in clearance of cell-free endotoxin has also been suggested based on studies with purified endotoxin aggregates and blood monocytes. Because the interaction of BPI with cell-free endotoxin, during infection, occurs mainly in tissue and most likely in the form of shed bacterial outer membrane vesicles (“blebs”), we examined the effect of BPI on interactions of metabolically labeled ([14C]-acetate) blebs purified from Neisseria meningitidis serogroup B with either human monocyte-derived macrophages or monocyte-derived dendritic cells (MDDC). BPI produced a dose-dependent increase (up to 3-fold) in delivery of 14C-labeled blebs to MDDC, but not to monocyte-derived macrophages in the presence or absence of serum. Both, fluorescently labeled blebs and BPI were internalized by MDDC under these conditions. The closely related LPS-binding protein, in contrast to BPI, did not increase association of the blebs with MDDC. BPI-enhanced delivery of the blebs to MDDC did not increase cell activation but permitted CD14-dependent signaling by the blebs as measured by changes in MDDC morphology, surface expression of CD80, CD83, CD86, and MHC class II and secretion of IL-8, RANTES, and IP-10. These findings suggest a novel role of BPI in the interaction of bacterial outer membrane vesicles with dendritic cells that may help link innate immune recognition of endotoxin to Ag delivery and presentation.
IFN-γ-Producing Dendritic Cells Are Important for Priming of Gut Intraepithelial Lymphocyte Response Against Intracellular Parasitic Infection
Authors: Moretto Magali M. , Weiss Louis M. , Combe Crescent L. , Khan Imtiaz A. 
Published: April 2014

AbstractThe importance of intraepithelial lymphocytes (IEL) in immunoprotection against orally acquired pathogens is being increasingly recognized. Recent studies have demonstrated that Ag-specific IEL can be generated and can provide an important first line of defense against pathogens acquired via oral route. However, the mechanism involved in priming of IEL remains elusive. Our current study, using a microsporidial model of infection, demonstrates that priming of IEL is dependent on IFN-γ-producing dendritic cells (DC) from mucosal sites. DC from mice lacking the IFN-γ gene are unable to prime IEL, resulting in failure of these cells to proliferate and lyse pathogen-infected targets. Also, treatment of wild-type DC from Peyer’s patches with Ab to IFN-γ abrogates their ability to prime an IEL response against Encephalitozoon cuniculi in vitro. Moreover, when incubated with activated DC from IFN-γ knockout mice, splenic CD8+ T cells are not primed efficiently and exhibit reduced ability to home to the gut compartment. These data strongly suggest that IFN-γ-producing DC from mucosal sites play an important role in the generation of an Ag-specific IEL response in the small intestine. To our knowledge, this report is the first demonstrating a role for IFN-γ-producing DC from Peyer’s patches in the development of Ag-specific IEL population and their trafficking to the gut epithelium.
Lymphoma Immunotherapy with CpG Oligodeoxynucleotides Requires TLR9 Either in the Host or in the Tumor Itself
Authors: Li Jiali , Song Wenru , Czerwinski Debra K. , Varghese Bindu , Uematsu Satoshi , Akira Shizuo , Krieg Arthur M. , Levy Ronald 
Published: April 2014

AbstractEstablished widely metastatic tumor was cured in a transplanted mouse B cell lymphoma model, by the combination of chemotherapy plus intratumoral injection of oligodeoxynucleotides containing unmethylated C-G motifs (CpG). This therapeutic effect required that the CpG be injected directly into the tumor and was dependent on CD8 T cells. Although the efficacy of CpG oligodeoxynucleotides has been thought to depend on the expression of TLR9, we unexpectedly found that tumor rejection did not require host expression of TLR9. By using a TLR9-deficient tumor and a TLR9KO host, we demonstrate that TLR9 expression either by the host or the tumor is required. These results indicate that activation of Ag presentation by cells within the tumor via TLR9 stimulation can be an effective form of immunotherapy. This study forms the basis of an ongoing clinical trial in patients with lymphoma.
C-Terminal Tail Phosphorylation of N-Formyl Peptide Receptor: Differential Recognition of Two Neutrophil Chemoattractant Receptors by Monoclonal Antibodies NFPR1 and NFPR2
Authors: Riesselman Marcia , Miettinen Heini M. , Gripentrog Jeannie M. , Lord Connie I. , Mumey Brendan , Dratz Edward A. , Stie Jamal , Taylor Ross M. , Jesaitis Algirdas J. 
Published: April 2014

Abstract
The N-formyl peptide receptor (FPR), a G protein-coupled receptor that binds proinflammatory chemoattractant peptides, serves as a model receptor for leukocyte chemotaxis. Recombinant histidine-tagged FPR (rHis-FPR) was purified in lysophosphatidyl glycerol (LPG) by Ni2+-NTA agarose chromatography to &gt;95% purity with high yield. MALDI-TOF mass analysis (&gt;36% sequence coverage) and immunoblotting confirmed the identity as FPR. The rHis-FPR served as an immunogen for the production of 2 mAbs, NFPR1 and NFPR2, that epitope map to the FPR C-terminal tail sequences, 305-GQDFRERLI-313 and 337-NSTLPSAEVE-346, respectively. Both mAbs specifically immunoblotted rHis-FPR and recombinant FPR (rFPR) expressed in Chinese hamster ovary cells. NFPR1 also recognized recombinant FPRL1, specifically expressed in mouse L fibroblasts. In human neutrophil membranes, both Abs labeled a 45–75 kDa species (peak Mr ∼60 kDa) localized primarily in the plasma membrane with a minor component in the lactoferrin-enriched intracellular fractions, consistent with FPR size and localization. NFPR1 also recognized a band of Mr ∼40 kDa localized, in equal proportions to the plasma membrane and lactoferrin-enriched fractions, consistent with FPRL1 size and localization. Only NFPR2 was capable of immunoprecipitation of rFPR in detergent extracts. The recognition of rFPR by NFPR2 is lost after exposure of cellular rFPR to f-Met-Leu-Phe (fMLF) and regained after alkaline phosphatase treatment of rFPR-bearing membranes. In neutrophils, NFPR2 immunofluorescence was lost upon fMLF stimulation. Immunoblotting ∼60 kDa species, after phosphatase treatment of fMLF-stimulated neutrophil membranes, was also enhanced. We conclude that the region 337–346 of FPR becomes phosphorylated after fMLF activation of rFPR-expressing Chinese hamster ovary cells and neutrophils.
The Cellular Immune Response to Mycobacterium tuberculosis Infection in the Guinea Pig
Authors: Ordway Diane , Palanisamy Gopinath , Henao-Tamayo Marcela , Smith Erin E. , Shanley Crystal , Orme Ian M. , Basaraba Randall J. 
Published: April 2014

Abstract
Pulmonary tuberculosis in guinea pigs is an extremely useful model for drug and vaccine testing due to the fact that its pathological disease process is similar to that present in humans. Progress in this field has been hindered because the tools necessary to undertake a complete immunological analysis of the guinea pig cellular immune response against Mycobacterium tuberculosis have been lacking. In this study, we combined a new flow cytometric gating strategy with immunohistochemistry to track T cells, B cells, and the MIL4 Ab, which detects both guinea pig heterophils (neutrophils) and eosinophils, to provide the first documentation of the kinetics of influx and positioning of these cell populations. The results show that the responding T cells are mostly CD4 cells and that after day 30 of the infection numbers of these cells in the lungs drops dramatically. These appear to be replaced by a steady increase in B cells and granulocytes which was associated with worsening lung pathology. These data reveal new information about the cellular phenotypes which mediate protective immunity or host immunopathogenesis during M. tuberculosis infection in this key animal model.
IL-1 Receptor Accessory Protein and ST2 Comprise the IL-33 Receptor Complex
Authors: Chackerian Alissa A. , Oldham Elizabeth R. , Murphy Erin E. , Schmitz Jochen , Pflanz Stefan , Kastelein Robert A. 
Published: April 2014

Abstract
IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(α and β) and IL-33 are discussed.
Inhibition of Experimental Allergic Airways Disease by Local Application of a Cell-Penetrating Dominant-Negative STAT-6 Peptide
Authors: McCusker Christine T. , Wang Yufa , Shan Jichuan , Kinyanjui Margaret W. , Villeneuve Annie , Michael Husheem , Fixman Elizabeth D. 
Published: April 2014

Abstract
Allergic airways disease is initiated and perpetuated by an aberrant Th2 inflammatory response regulated in part by the cytokines IL-4 and IL-13, each of which induces activation of the STAT-6 transcription factor. Data from murine models indicate that the clinical manifestations of acute asthma are STAT-6 dependent, and thus, STAT-6 is a target for drug development in allergic airways disease. We designed a novel chimeric peptide (STAT-6 inhibitory peptide (STAT-6-IP)) comprised of a sequence predicted to bind to and inhibit STAT-6, fused to a protein transduction domain, to facilitate cellular uptake of the STAT-6-binding peptide. Our data demonstrate that the STAT-6-IP inhibited OVA-induced production of Th2 cytokines IL-4 and IL-13 in vitro. In contrast, the STAT-6-IP did not affect production of IFN-γ, demonstrating specificity for Th2 cytokine inhibition. Following intranasal administration, the STAT-6-IP was localized to epithelial cells in the airways. Finally, in in vivo murine models of allergic rhinitis and asthma, intranasal delivery of the STAT-6-IP inhibited OVA-induced lung inflammation and mucus production as well as accumulation of eosinophils and IL-13 in bronchoalveolar lavage fluid and OVA-dependent airway hyperresponsiveness. Together these data show that local application of cell-penetrating peptide inhibitors of STAT-6 has significant potential for the treatment of allergic rhinitis and asthma.
Platelet Factor 4 (CXC Chemokine Ligand 4) Differentially Regulates Respiratory Burst, Survival, and Cytokine Expression of Human Monocytes by Using Distinct Signaling Pathways
Authors: Kasper Brigitte , Brandt Ernst , Brandau Sven , Petersen Frank 
Published: April 2014

Abstract
Platelet factor 4 (PF4; CXCL4) is an abundant platelet α-granule CXC chemokine with unique functions. Although lacking a chemotactic activity, PF4 initiates a signal transduction cascade in human monocytes leading to the induction of a broad spectrum of acute and delayed functions including phagocytosis, respiratory burst, survival, and the secretion of cytokines. Surprisingly, although these monocyte functions are well defined, only very limited information exists on the specific signaling pathways that are involved in the regulation of these biological responses. By using specific inhibitors and direct phosphorylation/activation studies, we show in the present study that PF4-mediated respiratory burst is dependent on a very rapid activation of PI3K, Syk, and p38 MAPK. Moreover, monocyte survival and differentiation instead is controlled by a delayed activation of Erk, with an activity peak after 6 h of stimulation. The inhibition of Erk completely reverted PF4-mediated protection against apoptosis. Finally, even though JNK is rapidly activated in PF4-treated monocytes, it is dispensable for the regulation of survival and respiratory burst. However, PF4-induced up-regulation of chemokine and cytokine mRNA and protein requires a sustained activation of JNK and Erk. Taken together, PF4-stimulated immediate monocyte functions (oxygen radical formation) are regulated by p38 MAPK, Syk, and PI3K, whereas delayed functions (survival and cytokine expression) are controlled by Erk and JNK.
Properdin Can Initiate Complement Activation by Binding Specific Target Surfaces and Providing a Platform for De Novo Convertase Assembly
Authors: Spitzer Dirk , Mitchell Lynne M. , Atkinson John P. , Hourcade Dennis E. 
Published: April 2014

Abstract
Complement promotes the rapid recognition and elimination of pathogens, infected cells, and immune complexes. The biochemical basis for its target specificity is incompletely understood. In this report, we demonstrate that properdin can directly bind to microbial targets and provide a platform for the in situ assembly and function of the alternative pathway C3 convertases. This mechanism differs from the standard model wherein nascent C3b generated in the fluid phase attaches nonspecifically to its targets. Properdin-directed complement activation occurred on yeast cell walls (zymosan) and Neisseria gonorrhoeae. Properdin did not bind wild-type Escherichia coli, but it readily bound E. coli LPS mutants, and the properdin-binding capacity of each strain correlated with its respective serum-dependent AP activation rate. Moreover, properdin:single-chain Ab constructs were used to direct serum-dependent complement activation to novel targets. We conclude properdin participates in two distinct complement activation pathways: one that occurs by the standard model and one that proceeds by the properdin-directed model. The properdin-directed model is consistent with a proposal made by Pillemer and his colleagues &gt;50 years ago.
Unchecked CD70 Expression on T Cells Lowers Threshold for T Cell Activation in Rheumatoid Arthritis
Authors: Lee Won-Woo , Yang Zhi-Zhang , Li Guangjin , Weyand Cornelia M. , Goronzy Jörg J. 
Published: April 2014

Abstract
Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4+CD28− and CD4+CD28+ T cells to discover disease-promoting activities of CD28− T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p &lt; 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4+CD28− T cells functioned by lowering the threshold for T cell activation; admixture of CD4+CD28− T cells augmented TCR-induced responses of autologous naive CD4+CD28+ T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.
Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature
Authors: Inokuma Margaret , dela Rosa Corazon , Schmitt Charles , Haaland Perry , Siebert Janet , Petry Douglas , Tang MengXiang , Suni Maria A. , Ghanekar Smita A. , Gladding Daiva , Dunne John F. , Maino Vernon C. , Disis Mary L. , Maecker Holden T. 
Published: April 2014

Abstract
The overall prevalence with which endogenous tumor Ags induce host T cell responses is unclear. Even when such responses are detected, they do not usually result in spontaneous remission of the cancer. We hypothesized that this might be associated with a predominant phenotype and/or cytokine profile of tumor-specific responses that is different from protective T cell responses to other chronic Ags, such as CMV. We detected significant T cell responses to CEA, HER-2/neu, and/or MAGE-A3 in 17 of 21 breast cancer patients naive to immunotherapy. The pattern of T cell cytokines produced in response to tumor-associated Ags (TAAs) in breast cancer patients was significantly different from that produced in response to CMV or influenza in the same patients. Specifically, there was a higher proportion of IL-2-producing CD8+ T cells, and a lower proportion of IFN-γ-producing CD4+ and/or CD8+ T cells responding to TAAs compared with CMV or influenza Ags. Finally, the phenotype of TAA-responsive CD8+ T cells in breast cancer patients was almost completely CD28+CD45RA− (memory phenotype). CMV-responsive CD8+ T cells in the same patients were broadly distributed among phenotypes, and contained a high proportion of terminal effector cells (CD27−CD28−CD45RA+) that were absent in the TAA responses. Taken together, these results suggest that TAA-responsive T cells are induced in breast cancer patients, but those T cells are phenotypically and functionally different from CMV- or influenza-responsive T cells. Immunotherapies directed against TAAs may need to alter these T cell signatures to be effective.
Neutrophils as a Novel Source of Eosinophil Cationic Protein in IgE-Mediated Processes
Authors: Monteseirín Javier , Vega Antonio , Chacón Pedro , Camacho M. Jesús , El Bekay Rajaa , Asturias Juan A. , Martínez Alberto , Guardia Pedro , Pérez-Cano Ramón , Conde José 
Published: April 2014

AbstractThe production of eosinophil cationic protein (ECP) in IgE-mediated diseases has been associated mainly with eosinophils, although no IgE-dependent ECP release has been observed in these cells. Because there is increasing evidence of neutrophil participation in allergic processes, we have examined whether human neutrophils from allergic patients were able to produce ECP by an IgE-dependent mechanism. After challenge with specific Ags to which the patients were sensitized, ECP release was detected in the culture medium. Furthermore, intracellular protein was detected by flow cytometry, immunofluorescence staining, and Western blotting. Expression at both mRNA and de novo protein synthesis were detected, respectively, by RT-PCR and radiolabeling with 35S. Ag effect was mimicked by cell treatment with anti-IgE Abs or Abs against FcεRI and galectin-3 (FcεRI&gt;galectin-3), but not against FcεRII. These observations represent a novel view of neutrophils as possible source of ECP in IgE-dependent diseases.
The Multitasking Mast Cell: Positive and Negative Roles in the Progression of Autoimmunity
Authors: Christy Alison L. , Brown Melissa A. 
Published: April 2014

Abstract
Among the potential outcomes of an aberrantly functioning immune system are allergic disease and autoimmunity. Although it has been assumed that the underlying mechanisms mediating these conditions are completely different, recent evidence shows that mast cells provide a common link. Mast cells reside in most tissues, are particularly prevalent at sites of Ag entry, and act as sentinel cells of the immune system. They express many inflammatory mediators that affect both innate and adaptive cellular function. They contribute to pathologic allergic inflammation but also serve an important protective role in bacterial and parasite infections. Given the proinflammatory nature of autoimmune responses, it is not surprising that studies using murine models of autoimmunity clearly implicate mast cells in the initiation and/or progression of autoimmune disease. In this review, we discuss the defined and hypothesized mechanisms of mast cell influence on autoimmune diseases, including their surprising and newly discovered role as anti-inflammatory cells.
PDGF Synergistically Enhances IFN-γ-Induced Expression of CXCL10 in Blood-Derived Macrophages: Implications for HIV Dementia
Authors: Dhillon Navneet Kaur , Peng Fuwang , Ransohoff Richard M. , Buch Shilpa 
Published: April 2014

Abstract
There is increasing cumulative evidence that activated mononuclear phagocytes (macrophages/microglia) releasing inflammatory mediators in the CNS are a better correlate of HIV-associated dementia (HAD) than the actual viral load in the brain. Earlier studies on simian HIV/rhesus macaque model of NeuroAIDS confirmed that pathological changes in brains of macaques with encephalitis were associated with up-regulation of platelet-derived growth factor (PDGF) and the chemokine, CXCL10. Because the complex interplay of inflammatory mediators released by macrophages often leads to the induction of neurotoxins in HAD, we hypothesized that PDGF could interact with IFN-γ to modulate the expression of CXCL10 in these primary virus target cells. Although PDGF alone had no effect on the induction of CXCL10 in human macrophages, in conjunction with IFN-γ, it significantly augmented the expression of CXCL10 RNA & protein through transcriptional and posttranscriptional mechanisms. Signaling molecules, such as JAK and STATs, PI3K, MAPK, and NF-κB were found to play a role in the synergistic induction of CXCL10. Furthermore, PDGF via its activation of p38 MAPK was able to increase the stability of IFN-γ-induced CXCL10 mRNA. Understanding the mechanisms involved in the synergistic up-regulation of CXCL10 could aid in the development of therapeutic modalities for HAD.
Novel Exosome-Targeted CD4+ T Cell Vaccine Counteracting CD4+25+ Regulatory T Cell-Mediated Immune Suppression and Stimulating Efficient Central Memory CD8+ CTL Responses
Authors: Hao Siguo , Liu Yongqing , Yuan Jinying , Zhang Xueshu , He Tianpei , Wu Xiaochu , Wei Yangdou , Sun Deming , Xiang Jim 
Published: April 2014

Abstract
T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4+ T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXOOVA) express exosomal peptide/MHC class I and costimulatory molecules. These EXOOVA-uptaken (targeted) CD4+ aT cells can stimulate CD8+ T cell proliferation and differentiation into central memory CD8+ CTLs and induce more efficient in vivo antitumor immunity and long-term CD8+ T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4+25+ regulatory T cell-mediated suppression of in vitro CD8+ T cell proliferation and in vivo CD8+ CTL responses and antitumor immunity. We further elucidate that the EXOOVA-uptaken (targeted)CD4+ aT cell’s stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8+ T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4+ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases.