bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Role for NF-κB Activation in Perforin Expression of NK Cells Upon IL-2 Receptor Signaling
Authors: Zhou Jun , Zhang Jin , Lichtenheld Mathias G. , Meadows Gary G. 
Published: April 2014

AbstractOptimal NK cell development and activation as well as cytolytic activity involves IL-2Rβ signals that also up-regulate expression of the pore-forming effector molecule perforin. Although the Jak/Stat pathway and specifically Stat5 transcription factors are required to promote many of the respective downstream events, the role of additional signaling pathways and transcription factors remains to be clarified. This report investigates the role of NF-κB activation for perforin expression by NK cells. It is demonstrated that IL-2-induced up-regulation of perforin in primary NK cells and in a model cell line is blocked by two pharmacological agents known to inhibit NF-κB activation. Direct evidence for the activation of the NF-κB pathway by IL-2R signals in NK cells involves activation of the IKKα kinase, inhibitory protein κBα degradation, nuclear translocation of p50/p65 complexes, and ultimately, transcriptional activation of the perforin gene via an NF-κB binding element in its upstream enhancer. Taken together, these observations strongly suggest that IL-2R signals can activate a pathway leading to NF-κB activation in NK cells and that this pathway is involved in the control of perforin expression.
C1q Regulatory Region Polymorphism Down-Regulating Murine C1q Protein Levels with Linkage to Lupus Nephritis
Authors: Miura-Shimura Yuko , Nakamura Kazuhiro , Ohtsuji Mareki , Tomita Hideaki , Jiang Yi , Abe Masaaki , Zhang Danqing , Hamano Yoshitomo , Tsuda Hiroshi , Hashimoto Hiroshi , Nishimura Hiroyuki , Taki Shinsuke , Shirai Toshikazu , Hirose Sachiko 
Published: April 2014

AbstractMuch of the pathology of systemic lupus erythematosus (SLE) is caused by deposition of immune complexes (ICs) into various tissues, including renal glomeruli. Because clearance of ICs depends largely on early complement component C1q, homozygous C1q deficiency is a strong genetic risk factor in SLE, although it is rare in SLE patients overall. In this work we addressed the issue of whether genetic polymorphisms affecting C1q levels may predispose to SLE, using the (NZB × NZW)F1 model. C1q genes are composed of three genes, C1qa, C1qc, and C1qb, arranged in this order, and each gene consists of two exons separated by one intron. Sequence analysis of the C1q gene in New Zealand Black (NZB), New Zealand White (NZW), and BALB/c mice showed no polymorphisms in exons and introns of three genes. However, Southern blot analysis revealed unique insertion polymorphism of a total of ∼3.5 kb in the C1qa upstream region of NZB mice. C1q levels in sera and culture supernatants of LPS-stimulated peritoneal macrophages and C1q messages in spleen cells were all lower in disease-free young NZB and (NZB × NZW)F1 mice than in age-matched non-autoimmune NZW and BALB/c mice. Quantitative trait loci analysis using (NZB × NZW)F1 × NZW backcrosses showed that NZB microsatellites in the vicinity of the C1q allele on chromosome 4 were significantly linked to low serum C1q levels and the development of nephritis. These data imply that not only C1q deficiency but also regulatory region polymorphisms down-regulating C1q levels may confer the risk for lupus nephritis by reducing IC clearance and thus promoting IC deposition in glomeruli.
The Vα14 NKT Cell TCR Exhibits High-Affinity Binding to a Glycolipid/CD1d Complex
Authors: Sidobre Stéphane , Naidenko Olga V. , Sim Bee-Cheng , Gascoigne Nicholas R. J. , Garcia K. Christopher , Kronenberg Mitchell 
Published: April 2014

AbstractMost CD1d-dependent NKT cells in mice have a canonical Vα14Jα18 TCR rearrangement. However, relatively little is known concerning the molecular basis for their reactivity to glycolipid Ags presented by CD1d. Using glycolipid Ags, soluble forms of a Vα14 NKT cell-derived TCR, and mutant and wild-type CD1d molecules, we probed the TCR/CD1d interaction by surface plasmon resonance, tetramer equilibrium staining, and tetramer staining decay experiments. By these methods, several CD1d α-helical amino acids could be defined that do not greatly alter lipid binding, but that affect the interaction with the TCR. Binding of the Vα14+ TCR to CD1d requires the agonist α-galactosylceramide (α-GalCer), as opposed to the nonantigenic β-galactosylceramide, although both Ags bind to CD1d, indicating that the carbohydrate moiety of the CD1d-bound Ag plays a major role in the TCR interaction. The TCR has a relatively high-affinity binding to the α-GalCer/CD1d complex, with a particularly slow off rate. These unique properties are consistent with the coreceptor-independent action of the Vα14 TCR and may be related to the intense response to α-GalCer by NKT cells in vivo.
Diversification of Ig Heavy Chain Genes in Human Preterm Neonates Prematurely Exposed to Environmental Antigens
Authors: Bauer Karl , Zemlin Michael , Hummel Michael , Pfeiffer Sabine , Karstaedt Julia , Steinhauser Gudrun , Xiao Xin , Versmold Hans , Berek Claudia 
Published: April 2014

AbstractPreterm neonates are exposed to extrauterine environmental Ags during the time period that corresponds to the last trimester of normal intrauterine development. To study whether this precocious exposure to Ags accelerates the Ig repertoire diversification, we compared IgH chain genes of preterm neonates (gestational age, 25–29 wk) during their first postnatal months with those of term neonates. Preterm infants approaching their expected date of delivery after 8–13 wk of extrauterine life used a similar VH, DH, and JH gene segment repertoire as term neonates born after intrauterine development. Furthermore, the length increase of the NDN region between VH and JH by 0.25 nt per gestational week (r = 0.556, p &lt; 0.0001) was not accelerated. Thus, the generation of the VH region gene repertoire is developmentally controlled and independent of environmental influences. However, exposure to extrauterine Ags induced class switch and somatic mutations in IgH chain genes within 2 wk after premature birth and IgG transcript diversity and mutational frequency increased with the duration of extrauterine life. Three-month-old preterm infants expressed a heterogeneous IgG repertoire at their expected date of delivery with VH region genes carrying significant numbers of somatic mutations with evidence for Ag selection. Term neonates, however, had no such IgG repertoire. We conclude that restrictions in the neonatal Ig VH region gene repertoire persist until term despite exposure to environmental Ags. Yet, many weeks before term the immune system of the preterm neonate can already support germinal center reactions in response to environmental Ags.
The Avian Chb6 Alloantigen Triggers Apoptosis in a Mammalian Cell Line
Authors: Pifer Jeannette , Robison Donald , Funk Phillip E. 
Published: April 2014

AbstractMany developing B lymphocytes are deleted by apoptosis. However, the mechanism signaling their demise remains poorly understood. Like mammals, chicken B cells are selected during their development; &gt;95% of the cells in the bursa of Fabricius die without entering the secondary immune system. The molecule chB6 (Bu-1) has been used as a marker to identify B cells in the chicken. ChB6 is a type I transmembrane glycoprotein whose function is enigmatic. We have provided evidence that chB6 can induce a rapid form of cell death exhibiting characteristics of apoptosis. Here we further examine cell death induced by chB6 in a transfected mouse cell line. ChB6 is shown to cause apoptosis in this cell line as detected by a TUNEL assay for DNA fragmentation. This apoptosis is subject to regulation by signals from growth factor or by Bcl-xL. Furthermore, we show that Ab binding to chB6 leads to cleavage of caspase 8, caspase 3, and poly(ADP ribose) polymerase. Overall, these data support the hypothesis that chB6 is a novel death receptor on avian B cells.
Isotype Can Affect the Fine Specificity of an Antibody for a Polysaccharide Antigen
Authors: McLean Gary R. , Torres Marcela , Elguezabal Natalia , Nakouzi Antonio , Casadevall Arturo 
Published: April 2014

Abstract
Ab specificity is determined by V region sequence. The murine Mab 18B7 (IgG1) binds to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan and produces annular immunofluorescence (IF) on yeast cells. The heavy and light V regions of 18B7 were expressed with the human C regions μ, γ1, γ2, γ3, γ4, and α1, and the specificity and binding properties of these mouse-human chimeric (ch) Abs was determined. The chIgG1, chIgG2, chIgG4, and the chIgA produced annular IF, whereas the IgM and IgG3 produced punctate IF, despite identical V region sequences. Competition experiments with murine Abs that competed with mAb 18B7 and binding assays to peptide mimetics of glucuronoxylomannan provided additional evidence for altered specificity in some of the ch Abs. Expression of 18B7 heavy V region with murine μ C region produced IgM with a punctate IF, indicating that a change in fine specificity also accompanied the change from murine IgG1 to IgM. Our results show that Ab fine specificity can be a function of isotype. This phenomenon may be most apparent for Abs that bind to Ag with repeating epitopes, such as polysaccharides, where the quarternary structure of the Ag-Ab complex may be influenced by such constraints as Fab-Fab angles, Fc-Fc interactions, Ab size, and solvent accessibility to exposed surfaces. Alterations in Ab fine specificity following isotype change could have important implications for current concepts on the generation of secondary Ab responses to certain Ags and for the isotype preference observed in Abs to polysaccharides.
The Chemokine ESkine/CCL27 Displays Novel Modes of Intracrine and Paracrine Function
Authors: Gortz Andreas , Nibbs Robert J. B. , McLean Pauline , Jarmin David , Lambie Wendy , Baird Janet W. , Graham Gerard J. 
Published: April 2014

Abstract
We have previously shown that the β-chemokine ESkine/CCL27 is differentially spliced to produce two alternative forms. One is a secreted chemokine (ESkine), whereas the other (PESKY) lacks a signal peptide and is translocated to the nucleus. The role of this nuclear-targeted chemokine has not so far been defined, and it was the purpose of this study to examine this chemokine variant in more depth. To identify the region of PESKY involved in the nuclear translocation we tagged fragments with enhanced green fluorescent protein and expressed them in Chinese hamster ovary cells. We show PESKY nuclear translocation to be dependent on C-terminal residues that are shared with the signal peptide-bearing variant ESkine. Indeed we further demonstrate that ESkine can also use these C-terminal residues to enter the nucleus of cells following receptor (CCR10)-mediated internalization. To examine biological roles for PESKY we have overexpressed it in 3T3 cells. Such overexpression results in marked cytoskeletal rearrangements that are coincident with a radical reorganization of the cellular actin cytoskeleton. Microarray analyses and Ab neutralization studies indicate that these changes are mediated in part by insulin-like growth factor-1. Furthermore, monolayer wounding assays indicate that PESKY expression correlates with markedly increased migratory capacity. Thus, it is our contention that nuclear PESKY and ESkine both enter the nucleus by either intracrine or paracrine mechanisms and may facilitate cellular migration by inducing actin cytoskeletal relaxation. Therefore, nuclear ESkine/PESKY represents a novel paradigm for chemokine function.
Structural Studies of Allelic Diversity of the MHC Class I Homolog MIC-B, a Stress-Inducible Ligand for the Activating Immunoreceptor NKG2D
Authors: Holmes Margaret A. , Li Pingwei , Petersdorf Effie W. , Strong Roland K. 
Published: April 2014

AbstractMIC-A and MIC-B are distant MHC class I homologs that serve as stress-inducible Ags on epithelial and epithelially derived cells. They are ligands for the widely expressed activating immunoreceptor NKG2D. To define the structural and functional consequences of sequence differences between MIC-A and MIC-B and between alleles of MIC-A and alleles of MIC-B, we determined the crystal structure of one allele of human MIC-B. Comparisons between the two previously reported MIC-A crystal structures and the MIC-B crystal structure show that, as expected, MIC-B is very similar in structure to MIC-A and likely interacts with NKG2D in an analogous manner. The interdomain flexibility observed in the MIC-A structures, a feature unique to MIC proteins among MHC class I proteins and homologs, is also displayed by MIC-B, with an interdomain relationship intermediate between the two examples of MIC-A structures. Mapping sequence variations onto the structures of MIC-A and MIC-B reveals patterns completely distinct from those displayed by classical MHC class I proteins, with a number of substitutions falling on positions likely to affect interactions with NKG2D, but with other positions lying distant from the NKG2D binding sites or buried within the core of the proteins.
Cross-Presentation ofListeria monocytogenes-Derived CD4 T Cell Epitopes
Authors: Škoberne Mojca , Schenk Simone , Hof Herbert , Geginat Gernot 
Published: April 2014

AbstractListeriolysin O (LLO) mediates the evasion of Listeria monocytogenes from the phagolysosome into the cytoplasm of the host cell. The recognition of infected cells by CD4 T cells is thought to be limited by the evasion of bacteria from the phagolysosome and also by the direct LLO-mediated inhibition of CD4 T cell activation. To analyze the influence of these immunoevasive mechanisms on the antilisterial CD4 T cell response, the expansion of L. monocytogenes-specific CD4 and CD8 T cells was monitored in infected mice. It was found that expansion of L. monocytogenes-specific CD4 T cells occurred synchronously with CD8 T cell expansion. The analysis of Ag presentation by macrophages and dendritic cells isolated from spleens of infected mice revealed efficient presentation of L. monocytogenes-derived CD4 T cell epitopes that was not dependent on the actA-mediated intercellular spread of bacteria. The further in vitro Ag presentation analysis revealed that although L. monocytogenes-infected macrophages and dendritic cells were poor presenters of CD4 T cell epitopes, more efficient presentation occurred after cocultivation of noninfected dendritic cells or macrophages with infected cells. These data indicate that the suppressive effect of LLO on the antilisterial CD4 T cell response is maintained only in infected APC and support the hypothesis that cross-priming plays a role in the induction of the strong CD4 T cell response in Listeria-infected mice.
The CXC Chemokine Murine Monokine Induced by IFN-γ (CXC Chemokine Ligand 9) Is Made by APCs, Targets Lymphocytes Including Activated B Cells, and Supports Antibody Responses to a Bacterial Pathogen In Vivo
Authors: Park Matthew K. , Amichay Doron , Love Paul , Wick Elizabeth , Liao Fang , Grinberg Alex , Rabin Ronald L. , Zhang Hongwei H. , Gebeyehu Senkuta , Wright Timothy M. , Iwasaki Akiko , Weng Youmin , DeMartino Julie A. , Elkins Karen L. , Farber Joshua M. 
Published: April 2014

AbstractMonokine induced by IFN-γ (Mig; CXC chemokine ligand 9) is an IFN-γ-inducible CXC chemokine that signals through the receptor CXCR3 and is known to function as a chemotactic factor for human T cells, particularly following T cell activation. The mig gene can be induced in multiple cell types and organs, and Mig has been shown to contribute to T cell infiltration into immune/inflammatory reactions in peripheral tissues in mice. We have investigated the expression and activities of Mig and CXCR3 in mouse cells and the role of Mig in models of host defense in mice. Murine (Mu)Mig functioned as a chemotactic factor for resting memory and activated T cells, both CD4+ and CD8+, and responsiveness to MuMig correlated with surface expression of MuCXCR3. Using mig−/− mice, we found that MuMig was not necessary for survival after infections with a number of intracellular pathogens. Surprisingly, however, we found that mig−/− mice showed reductions of 50–75% in Abs produced against the intracellular bacterium Francisella tularensis live vaccine strain. Furthermore, we found that MuMig induced both calcium signals and chemotaxis in activated B cells, and that B cell activation induced expression of MuCXCR3. In addition, IFN-γ induced the expression of mumig in APCs, including CD8α+ and CD8α− dendritic cells. Together, our data suggest that Mig and CXCR3 may be important not only to recruit T cells to peripheral inflammatory sites, but also in some cases to maximize interactions among activated T cells, B cells, and dendritic cells within lymphoid organs to provide optimal humoral responses to pathogens.
Marginal Zone Macrophages and Immune Responses Against Viruses
Authors: Oehen Stephan , Odermatt Bernhard , Karrer Urs , Hengartner Hans , Zinkernagel Rolf , López-Macías Constantino 
Published: April 2014

Abstract
The effective establishment of antiviral protection requires a coordinated interplay between the innate and adaptive immune system. Using osteopetrotic (op−/−) mice, this study investigated the influence of marginal zone macrophages in controlling and initiating a protective immune response against a cytopathic vs a non- or low-cytopathic virus. Despite the generation of potent adaptive immune responses, antiviral protection against cytopathic vesicular stomatitis virus critically depended on the presence of marginal zone macrophages. Infection with low doses (100 PFU) of non- or low-cytopathic lymphocytic choriomeningitis virus was rarely cleared and usually resulted in a carrier state in the majority of mice. This shows that the early innate immune system provides an important preparatory phase to the adaptive immune system and is particularly important for antiviral protection.
Effects of Rhinovirus Infection on Histamine and Cytokine Production by Cell Lines from Human Mast Cells and Basophils
Authors: Hosoda Masayoshi , Yamaya Mutsuo , Suzuki Tomoko , Yamada Norihiro , Kamanaka Masato , Sekizawa Kiyohisa , Butterfield Joseph H. , Watanabe Takehiko , Nishimura Hidekazu , Sasaki Hidetada 
Published: April 2014

Abstract
To understand the biochemical events that occur in the airways after rhinovirus (RV) infection, we developed for the first time a model in which the cell lines from human mast cells (HMC-1) and basophils (KU812) can be infected with RV14, a major group RV. Viral infection was confirmed by demonstrating that viral titers in culture supernatants, and RV RNA increased with time. RV14 infection alone and a combination of PMA plus calcium ionophore A23187, did not increase histamine production by these cells, although IgE plus anti-IgE increased the histamine production. However, histamine content in the supernatants increased in response to PMA plus A23187, or IgE plus anti-IgE after RV14 infection. PMA plus A23187 or IgE plus anti-IgE induced the production of IL-8 and GM-CSF in supernatants of HMC-1 cells and IL-4 and IL-6 in supernatants of KU812 cells. RV14 infection further increased the production of the cytokines, whereas RV14 infection alone did not alter the production of the cytokines by these cells. An Ab to ICAM-1 inhibited RV14 infection of the cells and decreased the production of cytokines and histamine after RV14 infection. RV14 infection enhanced the increases in intracellular calcium concentration and activation of NF-κB by PMA plus A23187 in the cells. These findings suggest that RV14 infection may prime the cytokine and histamine production from mast cells and basophils and may cause airway inflammation in asthma.
Long-Term Protective and Antigen-Specific Effect of Heat-Killed Mycobacterium vaccae in a Murine Model of Allergic Pulmonary Inflammation
Authors: Zuany-Amorim Claudia , Manlius Corinne , Trifilieff Alexandre , Brunet Laura R. , Rook Graham , Bowen Gareth , Pay Graham , Walker Christoph 
Published: April 2014

Abstract
This report examines the effect of heat-killed Mycobacterium vaccae in a mouse model of allergic pulmonary inflammation. The s.c. administration of M. vaccae 3 wk before the immunization significantly reduced Ag-induced airway hyperreactivity and the increase in the numbers of eosinophils observed in the bronchoalveolar lavage fluid, blood, and bone marrow, even though no detectable changes in either cytokine (IL-4, IL-13, IL-5, and IFN-γ) or total IgE levels were observed. Furthermore, transfer of splenocytes from OVA-immunized and M. vaccae-treated mice into recipient, OVA-immunized mice significantly reduced the allergen-induced eosinophilia by an IFN-γ-independent mechanism, clearly indicating that the mechanism by which M. vaccae induces its inhibitory effect is not due to a redirection from a predominantly Th2 to a Th1-dominated immune response. The protective effect of M. vaccae on the allergen-induced eosinophilia lasted for at least 12 wk after its administration, and the treatment was also effective in presensitized mice. Moreover, the allergen specificity of the inhibitory effect could be demonstrated using a double-immunization protocol, where M. vaccae treatment before OVA immunization had no effect on the eosinophilic inflammation induced by later immunization and challenge with cockroach extract Ag. Taken together, these results clearly demonstrate that M. vaccae is effective in blocking allergic inflammation by a mechanism independent of IFN-γ, induces long term and Ag-specific protection, and therefore has both prophylactic and therapeutic potential for the treatment of allergic diseases.
Stimulation by Toll-Like Receptors Inhibits Osteoclast Differentiation
Authors: Takami Masamichi , Kim Nacksung , Rho Jaerang , Choi Yongwon 
Published: April 2014

AbstractOsteoclasts, the cells capable of resorbing bone, are derived from hemopoietic precursor cells of monocyte-macrophage lineage. The same precursor cells can also give rise to macrophages and dendritic cells, which are essential for proper immune responses to various pathogens. Immune responses to microbial pathogens are often triggered because various microbial components induce the maturation and activation of immunoregulatory cells such as macrophages or dendritic cells by stimulating Toll-like receptors (TLRs). Since osteoclasts arise from the same precursors as macrophages, we tested whether TLRs play any role during osteoclast differentiation. We showed here that osteoclast precursors prepared from mouse bone marrow cells expressed all known murine TLRs (TLR1-TLR9). Moreover, various TLR ligands (e.g., peptidoglycan, poly(I:C) dsRNA, LPS, and CpG motif of unmethylated DNA, which act as ligands for TLR2, 3, 4, and 9, respectively) induced NF-κB activation and up-regulated TNF-α production in osteoclast precursor cells. Unexpectedly, however, TLR stimulation of osteoclast precursors by these microbial products strongly inhibited their differentiation into multinucleated, mature osteoclasts induced by TNF-related activation-induced cytokine. Rather, TLR stimulation maintained the phagocytic activity of osteoclast precursors in the presence of osteoclastogenic stimuli M-CSF and TNF-related activation-induced cytokine. Taken together, these results suggest that TLR stimulation of osteoclast precursors inhibits their differentiation into noninflammatory mature osteoclasts during microbial infection. This process favors immune responses and may be critical to prevent pathogenic effects of microbial invasion on bone.