bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets
Authors: Shalova Irina N. , Kajiji Tasneem , Lim Jyue Yuan , Gómez-Piña Vanesa , Fernández-Ruíz Irene , Arnalich Francisco , Iau Philip Tsau Choong , López-Collazo Eduardo , Wong Siew-Cheng , Biswas Subhra K. 
Published: March 2012

Abstract
Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16+) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R–associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16+ monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.
Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae
Authors: So Nancy S. Y. , Ostrowski Mario A. , Gray-Owen Scott D. 
Published: March 2012

Abstract
Neisseria gonorrhoeae, the cause of the sexually transmitted infection gonorrhea, elicits low levels of specific Ig that decline rapidly after the bacteria are cleared. Reinfection with the same serovar can occur, and prior gonococcal infection does not alter the Ig response upon subsequent exposure, suggesting that protective immunity is not induced. The mucosal Ig response apparent during gonorrhea does not correlate with that observed systemically, leading to a suggestion that it is locally generated. In considering whether N. gonorrhoeae directly influences B cells, we observed that gonococcal infection prolonged viability of primary human B cells in vitro and elicited robust activation and vigorous proliferative responses in the absence of T cells. Furthermore, we observed the specific expansion of IgD+CD27+ B cells in response to gonococcal infection. These cells are innate in function, conferring protection against diverse microbes by producing low-affinity, broadly reactive IgM without inducing classical immunologic memory. Although gonococcal infection of B cells produced small amounts of gonococcal-specific IgM, IgM specific for irrelevant Ags were also produced, suggesting a broad, polyspecific Ig response. The gonococci were effectively bound and engulfed by B cells. TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. To our knowledge, this is the first report of a bacterial pathogen having specific affinity for the human IgM memory B cells, driving their potent activation and polyclonal Ig response. This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea.
Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages
Authors: Nickel Daniel , Busch Martin , Mayer Daniel , Hagemann Benjamin , Knoll Valeska , Stenger Steffen 
Published: March 2012

Abstract
Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human β defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 ± 8% at 1% O2. We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human β defensin 2.
Lpa2 Is a Negative Regulator of Both Dendritic Cell Activation and Murine Models of Allergic Lung Inflammation
Authors: Emo Jason , Meednu Nida , Chapman Timothy J. , Rezaee Fariba , Balys Marlene , Randall Troy , Rangasamy Tirumalai , Georas Steve N. 
Published: March 2012

Abstract
Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2−/− mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF-κB–driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2−/− DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2−/− mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation.
Bcl6 and Maf Cooperate To Instruct Human Follicular Helper CD4 T Cell Differentiation
Authors: Kroenke Mark A. , Eto Danelle , Locci Michela , Cho Michael , Davidson Terence , Haddad Elias K. , Crotty Shane 
Published: March 2012

Abstract
Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. Transcriptional regulators of human Tfh cell differentiation are poorly understood. In this article, we demonstrate that Bcl6 controls specific gene modules for human Tfh cell differentiation. The introduction of Bcl6 expression in primary human CD4 T cells resulted in the regulation of a core set of migration genes that enable trafficking to germinal centers: CXCR4, CXCR5, CCR7, and EBI2. Bcl6 expression also induced a module of protein expression critical for T–B interactions, including SAP, CD40L, PD-1, ICOS, and CXCL13. This constitutes direct evidence for Bcl6 control of most of these functions and includes three genes known to be loci of severe human genetic immunodeficiencies (CD40L, SH2D1A, and ICOS). Introduction of Bcl6 did not alter the expression of IL-21 or IL-4, the primary cytokines of human Tfh cells. We show in this article that introduction of Maf (c-Maf) does induce the capacity to express IL-21. Surprisingly, Maf also induced CXCR5 expression. Coexpression of Bcl6 and Maf revealed that Bcl6 and Maf cooperate in the induction of CXCR4, PD-1, and ICOS. Altogether, these findings reveal that Bcl6 and Maf collaborate to orchestrate a suite of genes that define core characteristics of human Tfh cell biology.
Activated Mouse B Cells Lack Expression of Granzyme B
Authors: Hagn Magdalena , Belz Gabrielle T. , Kallies Axel , Sutton Vivien R. , Thia Kevin Y. , Tarlinton David M. , Hawkins Edwin D. , Trapani Joseph A. 
Published: March 2012

AbstractRecently, it has been reported that human B cells express and secrete the cytotoxic protease granzyme B (GrB) after stimulation with IL-21 and BCR cross-linking. To date, there are few clues on the function of GrB in B cell biology. As experimental transgenic murine systems should provide insights into these issues, we assayed for GrB in C57BL/6 B cells using an extensive array of physiologically relevant stimuli but were unable to detect either GrB expression or its proteolytic activity, even when Ag-specific transgenic BCRs were engaged. Similar results were also obtained with B cells from DBA/2, CBA, or BALB/c mice. In vivo, infection with either influenza virus or murine γ-herpesvirus induced the expected expression of GrB in CTLs, but not in B cell populations. We also investigated a possible role of GrB on the humoral immune response to the model Ag 4-hydroxy-3-nitrophenylacetyl–keyhole limpet hemocyanin, but GrB-deficient mice produced normal amounts of Ab with typical affinity maturation and a heightened secondary response, demonstrating conclusively the redundancy of GrB for Ab responses. Our results highlight the complex evolutionary differences that have shaped the immune systems of mice and humans. The physiological consequences of GrB expression in human B cells remain unclear, and the current study suggests that experimental mouse models will not be helpful in addressing this issue.
The Drosophila Protein Mustard Tailors the Innate Immune Response Activated by the Immune Deficiency Pathway
Authors: Wang Zhipeng , Berkey Cristin D. , Watnick Paula I. 
Published: March 2012

Abstract
In this study, we describe a Drosophila melanogaster transposon insertion mutant with tolerance to Vibrio cholerae infection and markedly decreased transcription of diptericin as well as other genes regulated by the immune deficiency innate immunity signaling pathway. We present genetic evidence that this insertion affects a locus previously implicated in pupal eclosion. This genetic locus, which we have named mustard (mtd), contains a LysM domain, often involved in carbohydrate recognition, and a TLDc domain of unknown function. More than 20 Mtd isoforms containing one or both of these conserved domains are predicted. We establish that the mutant phenotype represents a gain of function and can be replicated by increased expression of a short, nuclearly localized Mtd isoform comprised almost entirely of the TLDc domain. We show that this Mtd isoform does not block Relish cleavage or translocation into the nucleus. Lastly, we present evidence suggesting that the eclosion defect previously attributed to the Mtd locus may be the result of the unopposed action of the NF-κB homolog, Relish. Mtd homologs have been implicated in resistance to oxidative stress. However, to our knowledge this is the first evidence that Mtd or its homologs alter the output of an innate immunity signaling cascade from within the nucleus.
Innate Immunity Mediates Follicular Transport of Particulate but Not Soluble Protein Antigen
Authors: Link Alexander , Zabel Franziska , Schnetzler Yvonne , Titz Alexander , Brombacher Frank , Bachmann Martin F. 
Published: March 2012

Abstract
Ag retention on follicular dendritic cells (FDCs) is essential for B cell activation and clonal selection within germinal centers. Protein Ag is deposited on FDCs after formation of immune complexes with specific Abs. In this study, by comparing the same antigenic determinant either as soluble protein or virus-like particle (VLP), we demonstrate that VLPs are transported efficiently to murine splenic FDCs in vivo in the absence of prior immunity. Natural IgM Abs and complement were required and sufficient to mediate capture and transport of VLPs by noncognate B cells. In contrast, soluble protein was only deposited on FDCs in the presence of specifically induced IgM or IgG Abs. Unexpectedly, IgG Abs had the opposite effect on viral particles and inhibited FDC deposition. These findings identify size and repetitive structure as critical factors for efficient Ag presentation to B cells and highlight important differences between soluble proteins and viral particles.
Mapping of Clinical and Expression Quantitative Trait Loci in a Sex-Dependent Effect of Host Susceptibility to Mouse-Adapted Influenza H3N2/HK/1/68
Authors: Boivin Gregory A. , Pothlichet Julien , Skamene Emil , Brown Earl G. , Loredo-Osti J. Concepción , Sladek Robert , Vidal Silvia M. 
Published: March 2012

AbstractSeasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to severe influenza in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (QTL) and lung expression QTL mapping identified candidate genes for two sex-specific QTL on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the TNFR superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.
The SWI/SNF-like BAF Complex Is Essential for Early B Cell Development
Authors: Choi Jinwook , Ko Myunggon , Jeon Shin , Jeon Yoon , Park Kyungsoo , Lee Changjin , Lee Ho , Seong Rho H. 
Published: March 2012

Abstract
During the process of B cell development, transcription factors, such as E2A and Ebf1, have been known to play key roles. Although transcription factors and chromatin regulators work in concert to direct the expression of B lineage-specific genes, little is known about the involvement of regulators for chromatin structure during B lymphopoiesis. In this article, we show that deletion of Srg3/mBaf155, a scaffold subunit of the SWI/SNF-like BAF complex, in the hematopoietic lineage caused defects at both the common lymphoid progenitor stage and the transition from pre–pro-B to early pro-B cells due to failures in the expression of B lineage-specific genes, such as Ebf1 and Il7ra, and their downstream target genes. Moreover, mice that were deficient in the expression of Brg1, a subunit of the complex with ATPase activity, also showed defects in early B cell development. We also found that the expression of Ebf1 and Il7ra is directly regulated by the SWI/SNF-like BAF complex. Thus, our results suggest that the SWI/SNF-like BAF complex facilitates early B cell development by regulating the expression of B lineage-specific genes.
The TIGIT/CD226 Axis Regulates Human T Cell Function
Authors: Lozano Ester , Dominguez-Villar Margarita , Kuchroo Vijay , Hafler David A. 
Published: March 2012

Abstract
T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4+ T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-γ. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-γ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-γ with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease.
The Roles of the Ge‐Te Core Network and the Sb‐Te Pseudo Network During Rapid Nucleation‐Dominated Crystallization of Amorphous Ge2Sb2Te5
Authors: Ohara Koji , Temleitner László , Sugimoto Kunihisa , Kohara Shinji , Matsunaga Toshiyuki , Pusztai László , Itou Masayoshi , Ohsumi Hiroyuki , Kojima Rie , Yamada Noboru , Usuki Takeshi , Fujiwara Akihiko , Takata Masaki 
Published: March 2012

AbstractGe2Sb2Te5 (GST) has demonstrated its outstanding importance among rapid phase‐change (PC) materials, being applied for optical and electrical data storage for over three decades. The mechanism of nanosecond phase change in GST, which is vital for its application, has long been disputed: various, quite diverse scenarios have been proposed on the basis of various experimental and theoretical approaches. Nevertheless, one central question still remains unanswered: why is amorphous GST stable at room temperature for long time while it can rapidly transform to the crystalline phase at high temperature? Here it is revealed for the first time, by modelling the amorphous structure based on synchrotron radiation anomalous X‐ray scattering data, that germanium and tellurium atoms form a “core” Ge‐Te network with ring formation. It is also suggested that the Ge‐Te network can stabilize the amorphous phase at room temperature and can persist in the crystalline phase. On the other hand, antimony does not contribute to ring formation but constitutes a “pseudo” network with tellurium, in which the characteristic Sb–Te distance is somewhat longer than the covalent Sb–Te bond distance. This suggests that the Sb‐Te pseudo network may act as a precursor to forming critical nuclei during the crystallization process. The findings conclude that the Ge‐Te core network is responsible for the outstanding stability and rapid phase change of the amorphous phase while the Sb‐Te pseudo network is responsible for triggering critical nucleation.
Occupational rhinitis and asthma due to EDTA‐containing detergents or disinfectants
Authors: Laborde‐Castérot Hervé , Villa Antoine F. , Rosenberg Nicole , Dupont Patricia , Lee Hwee Min , Garnier Robert 
Published: March 2012

AbstractBackgroundDetergents and disinfectants are an emerging cause of work‐related rhinitis and asthma. These products may contain ethylenediamine tetraacetic acid (EDTA). The authors report 10 cases of EDTA‐related asthma and/or rhinitis.MethodsReview of the medical charts of patients who presented with work‐related rhinitis (alone or with asthma), with a history of exposure to aerosols of EDTA‐containing products and who underwent a nasal provocation test (NPT) with tetrasodium EDTA (1–4%) in our occupational health unit.ResultsTwenty‐eight patients underwent a NPT with EDTA, which was positive in 10 cases. These patients, mostly cleaners or healthcare workers, used spray formulations of cleaning products.ConclusionsThis case series is the first report of EDTA‐related respiratory disease, documented by a specific test. An irritant mechanism is unlikely. Further studies are required to distinguish between an immunoallergic response and a pharmacological mechanism possibly resulting from calcium chelation, as suggested by animal experiments. A ban of spray preparations would be sufficient to prevent respiratory disease induced by EDTA inhalation, regardless of its mechanism. Am. J. Ind. Med. 55:677–682, 2012. © 2012 Wiley Periodicals, Inc.
Thermal Hydrogen‐Atom Transfer from Methane: The Role of Radicals and Spin States in Oxo‐Cluster Chemistry
Authors: Dietl Nicolas , Schlangen Maria , Schwarz Helmut 
Published: March 2012

AbstractHydrogen‐atom transfer (HAT), as one of the fundamental reactions in chemistry, is investigated with state‐of‐the‐art gas‐phase experiments in conjunction with computational studies. The focus of this Minireview concerns the role that the intrinsic properties of gaseous oxo‐clusters play to permit HAT reactivity from saturated hydrocarbons at ambient conditions. In addition, mechanistic implications are discussed which pertain to heterogeneous catalysis. From these combined experimental/computational studies, the crucial role of unpaired spin density at the abstracting atom becomes clear, in distinct contrast to recent conclusions derived from solution‐phase experiments.
A new “tool” for transcatheter atrial defect closure: The St. Jude SL2™ sheath
Authors: Lee Simon , Sutton Nicole , Lopez Leo , Farooqi Kanwal , Mahgerefteh Joseph , Blancas Imelissa , Pass Robert H. 
Published: March 2012

AbstractBackgroundOrienting the left atrial disc of an atrial septal defect (ASD) closure device parallel to the septum is important, particularly in cases of ASD with deficient retroaortic rim. Standard vascular sheaths can make this challenging. We report the use of an electrophysiologic sheath, the SL2™ St. Jude Vascular sheath (St. Jude Medical, St. Paul, MN) for closure of ASD.MethodsAll patients undergoing ASD closure between July 2010 and February 2011 at The Children's Hospital at Montefiore in which the SL2 sheath was used were reviewed.ResultsNine patients underwent transcatheter ASD or PFO (1/9) closure with the SL2 sheath. Mean age was 22.7 years (range, 3–58); weight was 46.5 kg (range, 14.7–78.6). The Amplatzer ASD Occluder (AGA Medical Corp., Plymouth, MN) was used in all cases. The mean measurement of the ASDs via “stop‐flow” technique was 13.3 mm (range, 4–19). The mean device size was 13.9 mm (range, 5–20) or 105% the size of the defect. The retroaortic rim was deficient (<2 mm) in 3 of 9. ASD closure was achieved in 9 of 9. In all, the left atrial disk was brought toward the atrial septum parallel to the atrial septum, and repositioning or recapturing of the device was unnecessary in any case. Mean fluoroscopy time was 9.3 min (range, 2.2–18). No significant complications.ConclusionsThe SL2 sheath was useful to position the ASD device parallel to the atrial septum, eliminating the need for redeployment during the procedure. This sheath was useful in those cases of deficient retroaortic rim in this study. © 2012 Wiley Periodicals, Inc.