bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Recirculating B Cell Pool Contains Two Functionally Distinct, Long-Lived, Posttransitional, Follicular B Cell Populations
Authors: Cariappa Annaiah , Boboila Cristian , Moran Stewart T. , Liu Haoyuan , Shi Hai Ning , Pillai Shiv 
Published: April 2014

AbstractDisparate models for the development of peripheral B cells may reflect significant heterogeneity in recirculating long-lived B cells that have not been previously accounted for. We show in this study that the murine recirculating B cell pool contains two distinct, long-lived, posttransitional, follicular B cell populations. Follicular Type I IgMlow B cells require Ag-derived and Btk-dependent signals for their development and make up the majority of cells in the recirculating follicular B cell pool. Follicular type II B cells do not require Btk- or Notch-2-derived signals, make up about a third of the long-lived recirculating B cell pool, and can develop in the absence of Ag. These two follicular populations exhibit differences in basal tyrosine phosphorylation and in BCR-induced proliferation, suggesting that they may represent functionally distinct populations of long-lived recirculating B cells.
Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment
Authors: Subramanian Manikandan , Shaha Chandrima 
Published: April 2014

AbstractEstrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17β-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca2+ increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.
CTLs Contain and Use Intracellular Stores of FasL Distinct from Cytolytic Granules
Authors: He Jin-Shu , Ostergaard Hanne L. 
Published: April 2014

AbstractCTL lyse target cells through the release of cytolytic granule contents and cell surface expression of Fas ligand (FasL). Current models suggest that FasL is stored in cytolytic granules and that FasL cell surface expression would be subject to the same controls as degranulation. We demonstrate that murine CTLs undergo two waves of FasL cell surface expression after stimulation. The first wave is from a pre-existing pool of FasL, and the second wave requires new protein synthesis. Signaling for FasL expression appears to be finely tuned as a weak signal preferentially induced surface translocation of the stored FasL, whereas a strong signal preferentially triggered the expression of de novo synthesized FasL. The early FasL is differentially regulated from degranulation, as there were multiple circumstances whereby rapid FasL cell surface expression and FasL-dependent killing occurred in the absence of detectable degranulation. Furthermore, we found through confocal microscopy that stored FasL resides in vesicles distinct from cytolytic granules. Our data clearly show that CTL degranulation and FasL lytic mechanisms are fully independent with respect to stored component localization and regulation.
Induction and Function of Lipocalin Prostaglandin D Synthase in Host Immunity
Authors: Joo Myungsoo , Kwon Minjae , Sadikot Ruxana T. , Kingsley Philip J. , Marnett Lawrence J. , Blackwell Timothy S. , Peebles R. Stokes , Urade Yoshihiro , Christman John W. 
Published: April 2014

Abstract
Although mainly expressed in neuronal cells, lipocalin-type PGD synthase (L-PGDS) is detected in the macrophages infiltrated to atherosclerotic plaques. However, the regulation and significance of L-PGDS expression in macrophages are unknown. Here, we found that treatment of macrophages with bacterial endotoxin (LPS) or Pseudomonas induced L-PGDS expression. Epigenetic suppression of L-PGDS expression in macrophages blunted a majority of PGD2 produced after LPS treatment. Chromatin immunoprecipitation assays show that L-PGDS induction was regulated positively by AP-1, but negatively by p53. L-PGDS expression was detected in whole lung and alveolar macrophages treated with LPS or Pseudomonas. L-PGDS overexpressing transgenic mice improved clearance of Pseudomonas from the lung compared with nontransgenic mice. Similarly, intratracheal instillation of PGD2 enhanced removal of Pseudomonas from the lung in mice. In contrast, L-PGDS knockout mice were impaired in their ability to remove Pseudomonas from the lung. Together, our results identify induction of L-PGDS expression by inflammatory stimuli or bacterial infection, the regulatory mechanism of L-PGDS induction, and the protective role of L-PGDS expression in host immune response. Our study suggests a potential therapeutic usage of L-PGDS or PGD2 against Pseudomonas pneumonia.
Human Blood-Brain Barrier Disruption by Retroviral-Infected Lymphocytes: Role of Myosin Light Chain Kinase in Endothelial Tight-Junction Disorganization
Authors: Afonso Philippe Vicente , Ozden Simona , Prevost Marie-Christine , Schmitt Christine , Seilhean Danielle , Weksler Babette , Couraud Pierre-Olivier , Gessain Antoine , Romero Ignacio Andres , Ceccaldi Pierre-Emmanuel 
Published: April 2014

Abstract
The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1α and TNF-α secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-κB pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.
Cutting Edge: The IκB Kinase (IKK) Inhibitor, NEMO-Binding Domain Peptide, Blocks Inflammatory Injury in Murine Colitis
Authors: Shibata Wataru , Maeda Shin , Hikiba Yohko , Yanai Ayako , Ohmae Tomoya , Sakamoto Kei , Nakagawa Hayato , Ogura Keiji , Omata Masao 
Published: April 2014

Abstract
Inflammatory mediators such as TNF-α, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-κB. The aim of the present study was to investigate whether the NF-κB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IκB kinaseβ subunit (IKKβ) and inhibit NF-κB activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-κB activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-κB inhibition in both models. These results indicate that an IKKβ-targeted NF-κB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.
Cutting Edge: TNF-α-Converting Enzyme (TACE/ADAM17) Inactivation in Mouse Myeloid Cells Prevents Lethality from Endotoxin Shock
Authors: Horiuchi Keisuke , Kimura Tokuhiro , Miyamoto Takeshi , Takaishi Hironari , Okada Yasunori , Toyama Yoshiaki , Blobel Carl P. 
Published: April 2014

Abstract
TNF-α, a potent proinflammatory cytokine, is synthesized as a membrane-anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn’s disease, and endotoxin shock. The TNF-α converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases can also release TNF. Because TACE-deficient mice die shortly after birth, we generated conditional TACE-deficient mice to address whether TACE is the relevant sheddase for TNF in adult mice. In this study, we report that TACE inactivation in myeloid cells or temporal inactivation at 6 wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels. These findings corroborate that TACE is the major endotoxin-stimulated TNF sheddase in mouse myeloid cells in vivo, thereby further validating TACE as a principal target for the treatment of TNF-dependent pathologies.
Cutting Edge: Peyer’s Patch Plasmacytoid Dendritic Cells (pDCs) Produce Low Levels of Type I Interferons: Possible Role for IL-10, TGFβ, and Prostaglandin E2 in Conditioning a Unique Mucosal pDC Phenotype
Authors: Contractor Nikhat , Louten Jennifer , Kim Leesun , Biron Christine A. , Kelsall Brian L. 
Published: April 2014

Abstract
The organized lymphoid tissues of the intestine likely play an important role in the balance between tolerance harmless mucosal Ags and commensal bacteria and immunity to mucosal pathogens. We examined the phenotype and function of plasmacytoid dendritic cells (pDCs) from murine Peyer’s patches (PPs). When stimulated with CpG-enriched oligodeoxynucleotides in vitro, PPs and spleen pDCs made equivalent levels of IL-12, yet PP pDCs were incapable of producing significant levels of type I IFNs. Three regulatory factors associated with mucosal tissues, PGE2, IL-10, and TGFβ, inhibited the ability of spleen pDCs to produce type I IFN in a dose-dependent fashion. These studies suggest that mucosal factors may regulate the production of type I IFN as well as IL-12 by pDCs. In the intestine, this may be beneficial in preventing harmful innate and adaptive immune responses to commensal microorganisms.
Cutting Edge: Evidence of Direct TCR α-Chain Interaction with Superantigen
Authors: Pumphrey Nick , Vuidepot Annelise , Jakobsen Bent , Forsberg Göran , Walse Björn , Lindkvist-Petersson Karin 
Published: April 2014

Abstract
Superantigens are known to activate a large number of T cells. The SAg is presented by MHC class II on the APC and its classical feature is that it recognizes the variable region of the β-chain of the TCR. In this article, we report, by direct binding studies, that staphylococcal enterotoxin (SE) H (SEH), a bacterial SAg secreted by Staphylococcus aureus, instead recognizes the variable α-chain (TRAV27) of TCR. Furthermore, we show that different SAgs (e.g., SEH and SEA) can simultaneously bind to one TCR by binding the α-chain and the β-chain, respectively. Theoretical three-dimensional models of the penta complexes are presented. Hence, these findings open up a new dimension of the biology of the staphylococcal enterotoxins.
Antigen Transmission by Replicating Antigen-Bearing Dendritic Cells
Authors: Diao Jun , Winter Erin , Chen Wenhao , Xu Feng , Cattral Mark S. 
Published: April 2014

AbstractDuring steady-state conditions, conventional spleen dendritic cells (DC) turn over every 2–3 days. Recent evidence indicates that in situ proliferation of DC arising from immediate conventional DC precursors is an important contributor to their homeostasis. In this study, we report that replication-competent conventional DC precursors and DC can internalize and transfer model particulate and soluble Ags directly to their DC progeny during cell division. Real-time confocal microscopy and flow cytometry indicated that Ag transmission to progeny was symmetrical, and suggested that other mechanisms of inter-DC Ag transfer were not involved. Soluble protein Ags inherited by DC progeny were presented effectively to Ag-specific T lymphocytes. Furthermore, we show that the number of DC, and the proportion that are actively proliferating, expands several-fold during an immune response against a viral infection. Our results point to an unanticipated mechanism in which DC are continuously replaced from Ag-bearing replication-competent precursor cells that pass Ag molecules onto their progeny through successive cell divisions. Our findings help explain how Ag may persist in a population of DC despite the brief lifespan of individual mature DC.
CD8+ T Cell-Mediated Airway Hyperresponsiveness and Inflammation Is Dependent on CD4+IL-4+ T Cells
Authors: Koya Toshiyuki , Miyahara Nobuaki , Takeda Katsuyuki , Matsubara Shigeki , Matsuda Hiroyuki , Swasey Christina , Balhorn Annette , Dakhama Azzeddine , Gelfand Erwin W. 
Published: April 2014

Abstract
CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA257–264 peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4− T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell-dependent AHR and airway allergic inflammation.
Polylactide-Coglycolide Microspheres CoEncapsulating Recombinant Tandem Prion Protein with CpG-Oligonucleotide Break Self-Tolerance to Prion Protein in Wild-Type Mice and Induce CD4 and CD8 T Cell Responses
Authors: Kaiser-Schulz Gunnar , Heit Antje , Quintanilla-Martinez Leticia , Hammerschmidt Franziska , Hess Simone , Jennen Luise , Rezaei Human , Wagner Hermann , Schätzl Hermann M. 
Published: April 2014

Abstract
Prion diseases are fatal neurodegenerative diseases that are characterized by the conformational conversion of the normal, mainly α-helical cellular prion protein (PrP) into the abnormal β-sheet-rich infectious isoform (PrPSc). The immune system neither shows reaction against cellular PrP nor PrPSc, most likely due to profound self-tolerance. In previous studies, we were able to partly overcome self-tolerance using recombinantly expressed dimeric PrP (tandem PrP (tPrP)), in association with different adjuvants. Proof of principle for antiprion efficacy was obtained in vitro and in vivo. In this study, we demonstrate the induction of a specific Th1 T cell response in wild-type mice immunized with tPrP and CpG-oligonucleotide (ODN). Biochemical influences such as refolding conditions, ionic strength, pH, and interaction with CpG-ODN affected antigenic structure and thus improved immunogenicity. Furthermore, s.c. immunization with tPrP and CpG-ODN coencapsulated in biodegradable polylactide-coglycolide microspheres (PLGA-MS) enhanced CD4 T cell responses and, more prominent, the induction of CD8 T cells. In this vaccination protocol, PLGA-MS function as endosomal delivery device of Ag plus CpG-ODN to macrophages and dendritic cells. In contrast, PLGA-MS-based DNA vaccination approaches with a tPrP construct generated poor humoral and T cell responses. Our data show that prophylactic and therapeutic immunization approaches against prion infections might be feasible using tPrP Ag and CpG-ODN adjuvant without detectable side effects.
Tumors Hamper the Immunogenic Competence of CD4+ T Cell-Directed Dendritic Cell Vaccination
Authors: Zimmermann Valérie S. , Casati Anna , Schiering Chris , Caserta Stefano , Hess Michelini Rodrigo , Basso Veronica , Mondino Anna 
Published: April 2014

Abstract
Dendritic cells loaded with tumor-derived peptides induce protective CTL responses and are under evaluation in clinical trails. We report in this study that prophylactic administration of dendritic cells loaded with a MHC class II-restricted peptide derived from a model tumor Ag (Leishmania receptor for activated C kinase (LACK)) confers protection against LACK-expressing TS/A tumors, whereas therapeutic vaccination fails to cure tumor-bearing mice. Although CD4+ T cell-directed dendritic cell vaccination primed effector-like (CD44highCD62Llow, IL-2+, IFN-γ+) and central memory-like lymphocytes (CD44highCD62Lhigh, only IL-2+) in tumor-free mice, this was not the case in tumor-bearing animals in which both priming and persistence of CD4+ T cell memory were suppressed. Suppression was specific for the tumor-associated Ag LACK, and did not depend on CD25+ T cells. Because T cell help is needed for protective immunity, we speculate that the ability of tumors to limit vaccine-induced CD4+ T cell memory could provide a partial explanation for the limited efficacy of current strategies.
Immune Evasion of the Human Pathogen Pseudomonas aeruginosa: Elongation Factor Tuf Is a Factor H and Plasminogen Binding Protein
Authors: Kunert Anja , Losse Josephine , Gruszin Christin , Hühn Michael , Kaendler Kerstin , Mikkat Stefan , Volke Daniela , Hoffmann Ralf , Jokiranta T. Sakari , Seeberger Harald , Moellmann Ute , Hellwage Jens , Zipfel Peter F. 
Published: April 2014

Abstract
Pseudomonas aeruginosa is an opportunistic human pathogen that can cause a wide range of clinical symptoms and infections that are frequent in immunocompromised patients. In this study, we show that P. aeruginosa evades human complement attack by binding the human plasma regulators Factor H and Factor H-related protein-1 (FHR-1) to its surface. Factor H binds to intact bacteria via two sites that are located within short consensus repeat (SCR) domains 6–7 and 19–20, and FHR-1 binds within SCR domain 3–5. A P. aeruginosa Factor H binding protein was isolated using a Factor H affinity matrix, and was identified by mass spectrometry as the elongation factor Tuf. Factor H uses the same domains for binding to recombinant Tuf and to intact bacteria. Factor H bound to recombinant Tuf displayed cofactor activity for degradation of C3b. Similarly Factor H bound to intact P. aeruginosa showed complement regulatory activity and mediated C3b degradation. This acquired complement control was rather effective and acted in concert with endogenous proteases. Immunolocalization identified Tuf as a surface protein of P. aeruginosa. Tuf also bound plasminogen, and Tuf-bound plasminogen was converted by urokinase plasminogen activator to active plasmin. Thus, at the bacterial surface Tuf acts as a virulence factor and binds the human complement regulator Factor H and plasminogen. Acquisition of host effector proteins to the surface of the pathogen allows complement control and may facilitate tissue invasion.
Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence
Authors: Pandrea Ivona V. , Gautam Rajeev , Ribeiro Ruy M. , Brenchley Jason M. , Butler Isolde F. , Pattison Melissa , Rasmussen Terri , Marx Preston A. , Silvestri Guido , Lackner Andrew A. , Perelson Alan S. , Douek Daniel C. , Veazey Ronald S. , Apetrei Cristian 
Published: April 2014

AbstractThe predictive value of acute gut-associated lymphoid tissue (GALT) CD4+ T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4+ T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4+ T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4+ T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4+ T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4+ T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS.