bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Papillomavirus Type-16 Virus-Like Particles Activate Complementary Defense Responses in Key Dendritic Cell Subpopulations
Authors: Yang Rongcun , Murillo Francisco Martinez , Lin Ken-Yu , Yutzy William H. , Uematsu Satoshi , Takeda Kiyoshi , Akira Shizuo , Viscidi Raphael P. , Roden Richard B. S. 
Published: April 2014

AbstractHuman papillomavirus type-16 (HPV16) L1 virus-like particles (VLPs) activate dendritic cells (DCs) and induce protective immunity. In this study, we demonstrate, using global gene expression analysis, that HPV16 VLPs produce quite distinct innate responses in murine splenic DC subpopulations. While HPV16 VLPs increase transcription of IFN-γ and numerous Th1-related cytokines and chemokines in CD8α+CD11c+ DCs, CD4+CD11c+ DCs up-regulate only type I IFN and a different set of Th2-associated cytokines and chemokines. Type I IFN, but not IFN-γ, potentiates humoral immunity, notably production of VLP-specific IgG2a. However, HPV16 VLP-stimulated IL-12 production by CD8α+CD11c+ DCs is augmented by autocrine IFN-γ signaling. Thus, before adaptive immunity, HPV16 VLPs signal complementary defense responses in key DC subpopulations, indicating specialized DC lineages with predetermined polarization.
Functional Inactivation of Immature Dendritic Cells by the Intracellular Parasite Toxoplasma gondii
Authors: McKee Amy S. , Dzierszinski Florence , Boes Marianne , Roos David S. , Pearce Edward J. 
Published: April 2014

Abstract
Despite its noted ability to induce strong cellular immunity, and its known susceptibility to IFN-γ-dependent immune effector mechanisms, the protozoan Toxoplasma gondii is a highly successful parasite, able to replicate, disseminate, and either kill the host or, more commonly, establish resistant encysted life forms before the emergence of protective immune responses. We sought to understand how the parasite gains the advantage. Using transgenic clonal parasite lines engineered to express fluorescent markers in combination with dendritic cells (DC) grown from the bone marrow of wild-type mice or transgenic mice expressing fluorescent protein-tagged MHC class II molecules, we used flow cytometry and fluorescence microscopy to analyze the responses of infected DC to both invasion by the parasite and subsequent DC maturation signals. We found that T. gondii preferentially invades immature dendritic cells but fails to activate them in the process, and renders them resistant to subsequent activation by TLR ligands or the immune-system-intrinsic maturation signal CD40L. The functional consequences of T. gondii-mediated suppression of DC activation are manifested in a relative inability of infected immature DC to activate naive CD4+ Th lymphocytes, or to secrete cytokines, such IL-12 and TNF-α, that play important roles in innate and/or adaptive immunity. The findings reveal that T. gondii suppresses the ability of immature DC to participate in innate immunity and to induce adaptive immune responses. The ability of T. gondii to temporarily evade recognition could provide a selective advantage that permits dissemination and establishment before adaptive immune response initiation.
Mycobacterium tuberculosisLprG (Rv1411c): A Novel TLR-2 Ligand That Inhibits Human Macrophage Class II MHC Antigen Processing
Authors: Gehring Adam J. , Dobos Karen M. , Belisle John T. , Harding Clifford V. , Boom W. Henry 
Published: April 2014

AbstractMHC class II (MHC-II)-restricted CD4+ T cells are essential for control of Mycobacterium tuberculosis infection. This report describes the identification and purification of LprG (Rv1411c) as an inhibitor of primary human macrophage MHC-II Ag processing. LprG is a 24-kDa lipoprotein found in the M. tuberculosis cell wall. Prolonged exposure (&gt;16 h) of human macrophages to LprG resulted in marked inhibition of MHC-II Ag processing. Inhibition of MHC-II Ag processing was dependent on TLR-2. Short-term exposure (&lt;6 h) to LprG stimulated TLR-2-dependent TNF-α production. Thus, LprG can exploit TLR-2 signaling to inhibit MHC-II Ag processing in human macrophages. Inhibition of MHC-II Ag processing by mycobacterial lipoproteins may allow M. tuberculosis, within infected macrophages, to avoid recognition by CD4+ T cells.
A Secreted Protein from the Human Hookworm Necator americanus Binds Selectively to NK Cells and Induces IFN-γ Production
Authors: Hsieh George C.-F. , Loukas Alex , Wahl Allison M. , Bhatia Monica , Wang Yan , Williamson Angela L. , Kehn Kylene W. , Maruyama Haruhiko , Hotez Peter J. , Leitenberg David , Bethony Jeff , Constant Stephanie L. 
Published: April 2014

Abstract
Parasitic helminths induce chronic infections in their hosts although, with most human helminthiases, protective immunity gradually develops with age or exposure of the host. One exception is infection with the human hookworm, Necator americanus, where virtually no protection ensues over time. Such observations suggest these parasites have developed unique mechanisms to evade host immunity, leading us to investigate the role of the excretory/secretory (ES) products of adult N. americanus in manipulating host immune responses. Specifically, we found that a protein(s) from ES products of adult N. americanus bound selectively to mouse and human NK cells. Moreover, incubation of purified NK cells with N. americanus ES products stimulated the production of augmented (4- to 30-fold) levels of IFN-γ. This augmentation was dependent on the presence of both IL-2 and IL-12 and was endotoxin-independent. This is the first report of a pathogen protein that binds exclusively to NK cells and the first report of a nematode-derived product that induces abundant levels of cytokines from NK cells. Such an interaction could provide a means of cross-regulating deleterious Th2 immune responses in the host, thereby contributing to the long-term survival of N. americanus.
Suppression of Innate Immunity by Acute Ethanol Administration: A Global Perspective and a New Mechanism Beginning with Inhibition of Signaling through TLR3
Authors: Pruett Stephen B. , Schwab Carlton , Zheng Qiang , Fan Ruping 
Published: April 2014

Abstract
Excessive consumption of ethanol (EtOH) suppresses innate immunity, but the mechanisms have not been fully delineated. The present study was conducted to determine whether EtOH suppresses TLR signaling in vivo in mice and to characterize the downstream effects of such suppression. Degradation of IL-1R-associated kinase 1 induced by a TLR3 ligand in peritoneal cells (∼90% macrophages) was suppressed by EtOH. Phosphorylation of p38 kinase in peritoneal macrophages (F4/80+) was suppressed, as was nuclear translocation of p-c-Jun and p65 in peritoneal cells. EtOH decreased IL-6 and IL-12 (p40), but did not significantly affect IL-10 in peritoneal lavage fluid or in lysates of peritoneal cells. Changes in cytokine mRNAs (by RNase protection assay) in macrophages isolated by cell sorting or using Ficoll were generally consistent with changes in protein levels in cell lysates and peritoneal lavage fluid. Thus, suppression of TLR signaling and cytokine mRNA occurred in the same cells, and this suppression generally corresponded to changes in i.p. and intracellular cytokine concentrations. DNA microarray analysis revealed the suppression of an IFN-related amplification loop in peritoneal macrophages, associated with decreased expression of numerous innate immune effector genes (including cytokines and a chemokine also suppressed at the protein level). These results indicate that EtOH suppresses innate immunity at least in part by suppressing TLR3 signaling, suppressing an IFN-related amplification loop, and suppressing the induction of a wide range of innate effector molecules in addition to proinflammatory cytokines and chemokines.
The Induction of Acute Ileitis by a Single Microbial Antigen of Toxoplasma gondii
Authors: Rachinel Nicolas , Buzoni-Gatel Dominique , Dutta Chaitali , Mennechet Franck J. D. , Luangsay Souphalone , Minns Laurie A. , Grigg Michael E. , Tomavo Stanislas , Boothroyd John C. , Kasper Lloyd H. 
Published: April 2014

Abstract
The role of specific microbial Ags in the induction of experimental inflammatory bowel disease is poorly understood. Oral infection of susceptible C57BL/6 mice with Toxoplasma gondii results in a lethal ileitis within 7–9 days postinfection. An immunodominant Ag of T. gondii (surface Ag 1 (SAG1)) that induces a robust B and T cell-specific response has been identified and a SAG1-deficient parasite (Δsag1) engineered. We investigated the ability of Δsag1 parasite to induce a lethal intestinal inflammatory response in susceptible mice. C57BL/6 mice orally infected with Δsag1 parasites failed to develop ileitis. In vitro, the mutant parasites replicate in both enterocytes and dendritic cells. In vivo, infection with the mutant parasites was associated with a decrease in the chemokine and cytokine production within several compartments of the gut-associated cell population. RAG-deficient (RAG1−/−) mice are resistant to the development of the ileitis after T. gondii infection. Adoptive transfer of Ag-specific CD4+ effector T lymphocytes isolated from C57BL/6-infected mice into RAG−/− mice conferred susceptibility to the development of the intestinal disease. In contrast, CD4+ effector T lymphocytes from mice infected with the mutant Δsag1 strain failed to transfer the pathology. In addition, resistant mice (BALB/c) that fail to develop ileitis following oral infection with T. gondii were rendered susceptible following intranasal presensitization with the SAG1 protein. This process was associated with a shift toward a Th1 response. These findings demonstrate that a single Ag (SAG1) of T. gondii can elicit a lethal inflammatory process in this experimental model of pathogen-driven ileitis.
Impact of Fibronectin Fragments on the Transendothelial Migration of HIV-Infected Leukocytes and the Development of Subendothelial Foci of Infectious Leukocytes
Authors: Birdsall Holly H. , Porter Wendy J. , Green David M. , Rubio Jose , Trial JoAnn , Rossen Roger D. 
Published: April 2014

Abstract
Leukocyte infiltrates that can serve as viral reservoirs, and sites for viral replication are found in many organs of HIV-1-infected patients. Patients whose blood leukocytes migrate across confluent endothelial monolayers ex vivo and transmit infectious virus to mononuclear leukocytes (MNLs) lodged beneath this endothelial barrier have a worse prognosis. We evaluated the ability of 110- to 120-kDa fibronectin fragments (FNf), which are found in the blood of &gt;60% of HIV-1-infected patients, to stimulate transendothelial migration and drive productively infected MNLs into a potential perivascular space. FNf induced MNLs to release TNF-α in a dose-dependent fashion; the resulting increase in lymphocyte and monocyte transendothelial migration could be blocked with soluble TNF receptor I. Rather than penetrate deeply into the subendothelial matrix, as is seen with untreated controls, FNf-treated MNLs clustered just below the endothelial monolayer. Treatment with FNf during migration increased subsequent recovery of HIV-infected cells from the subendothelial compartment. FNf treatment also significantly increased the numbers of HLA-DRbright, dendritic-type cells that reverse-migrated from the subendothelial depot to the apical endothelial surface 48 h after migration. Fibronectin fragments can be produced by viral and host proteases in the course of inflammatory conditions. The ability of FNf to stimulate transendothelial migration of HIV-1-infected MNLs may help to explain the dissemination of this infection into cardiac, renal, and CNS tissues.
IL-9-Mediated Induction of Eotaxin1/CCL11 in Human Airway Smooth Muscle Cells
Authors: Gounni Abdelilah Soussi , Hamid Qutayba , Rahman Sahidur M. , Hoeck Jutta , Yang Jie , Shan Lianyu 
Published: April 2014

AbstractRecent work has shown the potential importance of IL-9 in allergic diseases. The development of transgenic mice overexpressing IL-9 has suggested a key role for this cytokine in the development of the asthmatic phenotype including airway eosinophilia. In this study, we evaluated the expression of the IL-9R and the effects of IL-9 on human ASM cells by examining the release of Th2-associated chemokines (eotaxin1/CCL11 and thymus- and activation-regulated chemokine (TARC)/CCL17). IL-9R α-chain mRNA and surface expression were detected in cultured human airway smooth muscle (ASM) cells. In addition, primary cultured ASM cells, as well as bronchial smooth muscle cells within biopsies of asthmatics and not control subjects, revealed IL-9R protein expression. IL-9 stimulation of human ASM cells resulted in release of eotaxin1/CCL11, but had no effect on the release of TARC/CCL17, in time- and dose-dependent manner. Moreover, in vitro chemotaxis assay demonstrated that conditioned medium from IL-9-stimulated ASM cells attracted human eosinophils. Neutralizing Abs to IL-9, but not to IL-4 or IL-13, reduced significantly IL-9-induced production of eotaxin1/CCL11 from ASM cells. Interestingly, real-time RT-PCR showed that IL-9 up-regulated eotaxin1/CCL11 mRNA expression, but had no effect on TARC/CCL17. Treatment with Act D abrogates IL-9-induced eotaxin1/CCL11 mRNA and protein release by ASM cells. Finally, transfection study using eotaxin1/CCL11 promoter luciferase construct confirmed that IL-9 induced eotaxin1/CCL11 at the transcriptional level. Taken together, these data provide new evidence demonstrating that IL-9-dependent activation of ASM cells contributes to eosinophilic inflammation observed in asthma.
Ex Vivo Homeostatic Proliferation of CD4+ T Cells in Rheumatoid Arthritis Is Dysregulated and Driven by Membrane-Anchored TNFα
Authors: Wagner Ulf , Pierer Matthias , Wahle Matthias , Moritz Falk , Kaltenhäuser Sylke , Häntzschel Holm 
Published: April 2014

AbstractThe systemic CD4+ T cell compartment in patients with rheumatoid arthritis (RA) is characterized by TCR repertoire contraction, shortened telomere lengths, and decreased numbers of recent thymic emigrants, suggesting a disturbed CD4+ T cell homeostasis. In mice, homeostatic proliferation of peripheral CD4+ T cells is regulated by TCR interaction with self peptide-MHC complexes (pMHC) and can be reproduced in vitro. We have established an ex vivo model of homeostatic proliferation, in which self-replication of human CD4+ T cells is induced by cell-cell contact with autologous monocytes. In healthy individuals, blockade of TCR-pMHC class II contact resulted in decreased CD4+ T cell division. In contrast, homeostatic proliferation in RA patients was not inhibited by pMHC blockade, but increased during the initial culture period. The anti-TNF-α Ab cA2 inhibited homeostasis-driven ex vivo proliferation in healthy controls and in RA patients. In addition, treatment of RA patients with infliximab decreased the ex vivo rate of homeostatic proliferation of CD4+ T cells. Our results suggest a disturbed regulation of CD4+ T cell homeostasis leading to the repertoire aberrations reported in RA. Membrane-anchored TNF-α appears to be a cell-cell contact-dependent stimulus of homeostatic proliferation of CD4+ T cells, possibly favoring self-replication of autoreactive CD4+ T cells in patients with RA.
Molecular Recognition Patterns of Serum Anti-DNA Topoisomerase I Antibody in Systemic Sclerosis
Authors: Hu Paul Q. , Fertig Noreen , Medsger Thomas A. , Wright Timothy M. 
Published: April 2014

Abstract
Autoreactive anti-DNA topoisomerase I (anti-Topo I) Abs are commonly detected in sera of systemic sclerosis (SSc) patients. Our studies have established a positive correlation between the levels of serum anti-Topo I Abs and both disease severity and activity of SSc. The molecular targets of anti-Topo I Ab on Topo I domains remain to be further defined. In this report, we studied the molecular recognition pattern of serum anti-Topo I Ab in 52 SSc patients. The highest reactivity of serum anti-Topo I Abs was against the core subdomains I and II (aa 207–441) and, to a lesser extent, against the core subdomain III (aa 433–636) of Topo I. The linker domain (aa 636–712) and the C-terminal domain (aa 713–765) had much less reactivity than the core domain (aa 207–636). Strikingly, very little reactivity was directed against the N-terminal domain (aa 1–213) by serum anti-Topo I Ab. This molecular recognition pattern was consistent among all SSc serum samples studied. Results from patients with serial serum samples indicated that this pattern remained unchanged over time. Interestingly, some naive B cells from healthy controls, upon transformation by EBV, produced IgM Abs against Topo I. These Abs had low affinity for Topo I and reacted equally to all domains of Topo I. The molecular recognition pattern of serum anti-Topo I Ab in SSc suggests the presence of a unique antigenic stimulation in vivo in this disease.
Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses
Authors: Cignetti Alessandro , Vallario Antonella , Roato Ilaria , Circosta Paola , Allione Bernardino , Casorzo Laura , Ghia Paolo , Caligaris-Cappio Federico 
Published: April 2014

Abstract
Primary acute myeloid leukemia cells can be induced to differentiate into dendritic cells (DC). In the presence of GM-CSF, TNF-α, and/or IL-4, leukemia-derived DC are obtained that display features of immature DC (i-DC). The aim of this study was to determine whether i-DC of leukemic origin could be further differentiated into mature DC (m-DC) and to evaluate the possibility that leukemic m-DC could be effective in vivo as a tumor vaccine. Using CD40L as maturating agent, we show that leukemic i-DC can differentiate into cells that fulfill the phenotypic criteria of m-DC and, compared with normal counterparts, are functionally competent in vitro in terms of: 1) production of cytokines that support T cell activation and proliferation and drive Th1 polarization; 2) generation of autologous CD8+ CTLs and CD4+ T cells that are MHC-restricted and leukemia-specific; 3) migration from tissues to lymph nodes; 4) amplification of Ag presentation by monocyte attraction; 5) attraction of naive/resting and activated T cells. Irradiation of leukemic i-DC after CD40L stimulation did not affect their differentiating and functional capacity. Our data indicate that acute myeloid leukemia cells can fully differentiate into functionally competent m-DC and lay the ground for testing their efficacy as a tumor vaccine.
Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity
Authors: Vasu Chenthamarakshan , Prabhakar Bellur S. , Holterman Mark J. 
Published: April 2014

Abstract
CTLA-4 (CD152) is actively involved in down-regulating T cell activation and maintaining lymphocyte homeostasis. Our earlier studies showed that targeted engagement of CTLA-4 can down-modulate T cell response and suppress allo- and autoimmune responses. In this study, we report that targeted CTLA-4 engagement can induce immune tolerance to a specific target through selective induction of an Ag-specific CD4+CD25+CTLA-4high regulatory T cell (Treg cell) population. Allogeneic cells coated with anti-CTLA-4 Ab induced immune hyporesponsiveness through suppression of proinflammatory cytokines IFN-γ and IL-2, and up-regulation of the regulatory cytokines IL-10, TGF-β1, and IL-4, presumably through the engagement of CTLA-4 on activated T cells. Although rechallenge with alloantigen failed to break the unresponsiveness, a transient recovery from tolerance was observed in the presence of high concentrations of exogenous IL-2, saturating concentrations of neutralizing anti-TGF-β1 and anti-IL-10 Abs, and blocking anti-CTLA-4 Ab, and upon depletion of CD4+CD25+ Treg cells. The CD4+CD25+CTLA-4high Treg cells from tolerant mice suppressed the effector function of CD25− T cells from Ag-primed mice. Adoptive transfer of these Treg cells into Ag-primed mice resulted in a significantly reduced alloantigen-specific response. Further characterization demonstrated that the Treg cells with memory phenotype (CD62L−) were more potent in suppressing the alloantigen-specific T cell response. These results strongly support that the targeted engagement of CTLA-4 has therapeutic potential for the prevention of transplant rejection.
Effects of Cytokines on Acetylcholine Receptor Expression: Implications for Myasthenia Gravis
Authors: Poëa-Guyon Sandrine , Christadoss Premkumar , Le Panse Rozen , Guyon Thierry , De Baets Marc , Wakkach Abdelilah , Bidault Jocelyne , Tzartos Socrates , Berrih-Aknin Sonia 
Published: April 2014

AbstractMyasthenia gravis is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study, we investigated the processes that may lead to thymic overexpression of the triggering Ag, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared with age- and sex-matched normal thymus controls. Therefore, we investigated whether proinflammatory cytokines could locally modify AChR expression in myoid and thymic epithelial cells. We found that AChR transcripts are up-regulated by IFN-γ, and even more so by IFN-γ and TNF-α, as assessed by real-time RT-PCR, with the α-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in thymic epithelial cells and at the membrane in myoid cells. To examine whether IFN-γ could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-γ gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared with wild-type mice. However, up-regulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-α. Altogether, these results indicate that proinflammatory cytokines influence the expression of AChR in vitro and in vivo. Because proinflammatory cytokine activity is evidenced in the thymus of myasthenia gravis patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.
TGF-β1 Uses Distinct Mechanisms to Inhibit IFN-γ Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet
Authors: Lin Jack T. , Martin Stacey L. , Xia Luxi , Gorham James D. 
Published: April 2014

Abstract
TGF-β1 plays a critical role in restraining pathogenic Th1 autoimmune responses in vivo, but the mechanisms that mediate TGF-β1’s suppressive effects on CD4+ T cell expression of IFN-γ expression remain incompletely understood. To evaluate mechanisms by which TGF-β1 inhibits IFN-γ expression in CD4+ T cells, we primed naive wild-type murine BALB/c CD4+ T cells in vitro under Th1 development conditions in the presence or the absence of added TGF-β1. We found that the presence of TGF-β1 during priming of CD4+ T cells suppressed both IFN-γ expression during priming as well as the development of Th1 effector cells expressing IFN-γ at a recall stimulation. TGF-β1 inhibited the development of IFN-γ-expressing cells in a dose-dependent fashion and in the absence of APC, indicating that TGF-β1 can inhibit Th1 development by acting directly on the CD4+ T cell. During priming, TGF-β1 strongly inhibited the expression of both T-bet (T box expressed in T cells) and Stat4. We evaluated the importance of these two molecules in the suppression of IFN-γ expression at the two phases of Th1 responses. Enforced expression of T-bet by retrovirus prevented TGF-β1’s inhibition of Th1 development, but did not prevent TGF-β1’s inhibition of IFN-γ expression at priming. Conversely, enforced expression of Stat4 partly prevented TGF-β1’s inhibition of IFN-γ expression during priming, but did not prevent TGF-β1’s inhibition of Th1 development. These data show that TGF-β1 uses distinct mechanisms to inhibit IFN-γ expression in CD4+ T cells at priming and at recall.