bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABrugia malayiHomolog of Macrophage Migration Inhibitory Factor Reveals an Important Link Between Macrophages and Eosinophil Recruitment During Nematode Infection
Authors: Falcone Franco H. , Loke P’ng , Zang Xingxing , MacDonald Andrew S. , Maizels Rick M. , Allen Judith E. 
Published: April 2014

AbstractInfections with the helminth parasite Brugia malayi share many key features with Th2-mediated allergic diseases, including recruitment of eosinophils. We have investigated the dynamics of inflammatory cell recruitment under type 2 cytokine conditions in mice infected with B. malayi. Among the cells recruited to the site of infection is a novel population of “alternatively activated” macrophages that ablate cell proliferation and enhance Th2 differentiation. By profiling gene expression in this macrophage population, we found a dramatic up-regulation of a recently described eosinophil chemotactic factor, eosinophil chemotactic factor-L/Ym1, representing over 9% of clones randomly selected from a cDNA library. Because B. malayi is known to secrete homologs (Bm macrophage migration inhibitory factor (MIF)-1 and -2) of the human cytokine MIF, we chose to investigate the role this cytokine mimic may play in the development of the novel macrophage phenotype observed during infection. Strikingly, administration of soluble recombinant Bm-MIF-1 was able to reproduce the effects of live parasites, leading both to the up-regulation of Ym1 by macrophages and a marked recruitment of eosinophils in vivo. Because activity of Bm-MIF-1 is dependent upon an amino-terminal proline, this residue was mutated to glycine; the resultant recombinant (Bm-MIF-1G) was unable to induce Ym1 transcription in macrophages or to mediate the recruitment of eosinophils. These data suggest that macrophages may provide a crucial link between helminth parasites, their active cytokine mimics, and the recruitment of eosinophils in infection.
Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion
Authors: Zouki Christine , Haas Barbara , Chan John S. D. , Potempa Lawrence A. , Filep János G. 
Published: April 2014

AbstractThe classic acute-phase reactant C-reactive protein (CRP) is a cyclic pentameric protein that diminishes neutrophil accumulation in inflamed tissues. When the pentamer is dissociated, CRP subunits undergo conformational rearrangement that results in expression of a distinctive isomer with unique antigenic and physicochemical characteristics (termed modified CRP (mCRP)). Recently, mCRP was detected in the wall of normal human blood vessels. We studied the impact and mechanisms of action of mCRP on expression of adhesion molecules on human neutrophils and their adhesion to human coronary artery endothelial cells. Both CRP and mCRP (0.1–200 μg/ml) down-regulated neutrophil l-selectin expression in a concentration-dependent fashion. Furthermore, mCRP, but not CRP, up-regulated CD11b/CD18 expression and stimulated neutrophil extracellular signal-regulated kinase activity, which was accompanied by activation of p21ras oncoprotein, Raf-1, and mitogen-activated protein kinase kinase. These actions of mCRP were sensitive to the mitogen-activated protein kinase kinase inhibitor PD98059. mCRP markedly enhanced attachment of neutrophils to LPS-activated human coronary artery endothelial when added together with neutrophils. This effect of mCRP was attenuated by an anti-CD18 mAb. Thus, loss of pentameric symmetry in CRP is associated with appearance of novel bioactivities in mCRP that enhance neutrophil localization and activation at inflamed or injured vascular sites.
Role of Sulfation in CD44-Mediated Hyaluronan Binding Induced by Inflammatory Mediators in Human CD14+ Peripheral Blood Monocytes
Authors: Brown Kelly L. , Maiti Arpita , Johnson Pauline 
Published: April 2014

AbstractActivation of T cells by Ag or stimulation of monocytes with inflammatory cytokines induces CD44 to bind to hyaluronan (HA), an adhesion event implicated in leukocyte-leukocyte, leukocyte-endothelial cell, and leukocyte-stromal cell interactions. We have previously shown that TNF-α induces CD44 sulfation in a leukemic cell line, which correlated with the induction of HA binding and CD44-mediated adhesion. In this study, we establish that TNF-α and IFN-γ induce HA binding and the sulfation of CD44 in CD14+ PBMC, whereas no induced HA binding or CD44 sulfation was observed in CD14− PBMC stimulated with TNF-α. Treatment of cells with NaClO3, an inhibitor of sulfation, prevented HA binding in a significant percentage of CD14+ PBMC induced by TNF-α, LPS, IL-1β, or IFN-γ. Furthermore, stimulation with TNF-α or IFN-γ in the presence of NaClO3 reduced the ability of isolated CD44H to bind HA, demonstrating a direct effect of CD44H sulfation on HA binding. In contrast, the transient induction of HA binding in T cells by PHA was not affected by NaClO3, suggesting that activated T cells do not use sulfation as a mechanism to regulate HA binding. Overall, these results demonstrate that inducible sulfation of CD44H is one mechanism used by CD14+ peripheral blood monocytes to induce HA binding in response to inflammatory agents such as TNF-α and IFN-γ.
Cross-Talk Between IL-1 and IL-6 Signaling Pathways in Rheumatoid Arthritis Synovial Fibroblasts
Authors: Deon David , Ahmed Simi , Tai Katy , Scaletta Nicholas , Herrero Carmen , Lee In-Hong , Krause Anja , Ivashkiv Lionel B. 
Published: April 2014

AbstractThe balance between pro- and anti-inflammatory cytokines plays an important role in determining the severity of inflammation in rheumatoid arthritis (RA). Antagonism between opposing cytokines at the level of signal transduction plays an important role in many other systems. We have begun to explore the possible contribution of signal transduction cross-talk to cytokine balance in RA by examining the effects of IL-1, a proinflammatory cytokine, on the signaling and action of IL-6, a pleiotropic cytokine that has both pro- and anti-inflammatory actions, in RA synovial fibroblasts. Pretreatment with IL-1 suppressed Janus kinase-STAT signaling by IL-6, modified patterns of gene activation, and blocked IL-6 induction of tissue inhibitor of metalloproteases 1 expression. These results suggest that proinflammatory cytokines may contribute to pathogenesis by modulating or blocking signal transduction by pleiotropic or anti-inflammatory cytokines. The mechanism of inhibition did not require de novo gene activation and did not depend upon tyrosine phosphatase activity, but, instead, was dependent on the p38 stress kinase. These results identify a molecular basis for IL-1 and IL-6 cross-talk in RA synoviocytes and suggest that, in addition to levels of cytokine expression, modulation of signal transduction also plays a role in regulating cytokine balance in RA.
Dominant Autoimmune Epitopes Recognized by Pemphigus Antibodies Map to the N-Terminal Adhesive Region of Desmogleins
Authors: Sekiguchi Maiko , Futei Yuko , Fujii Yoshiko , Iwasaki Toshiro , Nishikawa Takeji , Amagai Masayuki 
Published: April 2014

AbstractDesmoglein (Dsg) is a cadherin-type adhesion molecule found in desmosomes. Dsg1 and Dsg3 are the target Ags in the autoimmune blistering diseases pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively. To map conformational epitopes of Dsg1 and Dsg3 in PF and PV, we generated Dsg1- and Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg1-specific residues by baculovirus expression. The swapped domains were portions of the N-terminal extracellular domains of Dsg1 (1–496) and Dsg3 (1–566), which have similar structures but distinct epitopes. The binding of autoantibodies to the mutant molecules was assessed by competition ELISAs. Domain-swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 yielded &gt;50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera, respectively. Furthermore, removal of Abs against the 161 N-terminal residues of Dsg1 by immunoadsorption eliminated the ability of PF sera to induce cutaneous blisters in neonatal mice. Within these N-terminal regions, most of the epitopes were mapped to residues 26–87 of Dsg1 and 25–88 of Dsg3. Furthermore, a point-mutated Dsg3 molecule containing Dsg1-specific amino acid substitutions (His25, Cys28, Ala29) reacted with anti-Dsg1 IgG, thus defining one of the epitopes of Dsg1. Using the predicted three-dimensional structure of classic cadherins as a model, these findings suggest that the dominant autoimmune epitopes in both PF and PV are found in the N-terminal adhesive surfaces of Dsgs.
Autoantibodies to the Amino-Terminal Fragment of β-Fodrin Expressed in Glandular Epithelial Cells in Patients with Sjögren’s Syndrome
Authors: Kuwana Masataka , Okano Tetsuroh , Ogawa Yoko , Kaburaki Junichi , Kawakami Yutaka 
Published: April 2014

Abstract
Sjögrens’s syndrome (SS) is an autoimmune disease characterized by destruction of lacrimal and salivary glands, but the mechanisms underlying the disease process are unclear. By immunoscreening a HepG2 cDNA library with serum from an SS patient we isolated a cDNA encoding amino-terminal 616 aa of β-fodrin, a membrane skeleton protein associated with ion channels and pumps. Serum Ab to the amino-terminal fragment of β-fodrin was frequently detected in SS patients compared with rheumatic disease patients without SS or healthy controls (70 vs 12 or 4%; p &lt; 0.00001). All the anti-β-fodrin-positive sera recognized the amino-terminal fragment with no homology to α-fodrin. Anti-β-fodrin Abs in patients’ sera as well as mouse polyclonal sera raised against the amino-terminal β-fodrin fragment did not react with intact β-fodrin, but recognized the 65-kDa amino-terminal fragment generated through cleavage by caspase-3 or granzyme B. When expression of intact and fragmented β-fodrin in lacrimal glands was assessed by immunohistochemistry, the antigenic amino-terminal fragment was distributed diffusely in acinar epithelial cell cytoplasm, whereas the carboxyl-terminal fragment and/or intact β-fodrin were localized in peripheral cytoplasm, especially at the basal membrane, in SS patients. In contrast, intact β-fodrin was detected primarily at the apical membrane of epithelia, and the amino-terminal fragment was scarcely detected in control patients with chronic graft-vs-host disease. These findings suggest that cleavage and altered distribution of β-fodrin in glandular epithelial cells may induce impaired secretory function and perpetuate an autoimmune response to β-fodrin, leading to autoantibody production and glandular destruction in SS.
Molecular and Immunological Characterization of Arginine Kinase from the Indianmeal Moth,Plodia interpunctella, a Novel Cross-Reactive Invertebrate Pan-Allergen
Authors: Binder Marina , Mahler Vera , Hayek Brigitte , Sperr Wolfgang R. , Schöller Matthias , Prozell Sabine , Wiedermann Gerhard , Valent Peter , Valenta Rudolf , Duchêne Michael 
Published: April 2014

AbstractIgE recognition of indoor allergens represents a major cause of allergic asthma in atopic individuals. We found that 52 of 102 patients suffering from allergic symptoms indoors contained IgE Abs against allergens from the Indianmeal moth (Plodia interpunctella), a ubiquitous food pest. Using serum IgE from a moth-sensitized patient we screened an expression cDNA library constructed from P. interpunctella larvae. cDNAs coding for arginine kinase (EC 2.7.3.3), a 40-kDa enzyme commonly occurring in invertebrates that is involved in the storage of such high-energy phosphate bonds as phosphoarginine, were isolated. Recombinant moth arginine kinase, designated Plo i 1, was expressed in Escherichia coli as a histidine-tagged protein with enzymatic activity, and purified to homogeneity by nickel chelate affinity chromatography. Purified recombinant arginine kinase induced specific basophil histamine release and immediate as well as late-phase skin reactions. It reacted with serum IgE from 13 of the 52 (25%) moth-allergic patients and inhibited the binding of allergic patients’ IgE to an immunologically related 40-kDa allergen present in house dust mite, cockroach, king prawn, lobster, and mussel. Our results indicate that arginine kinases represent a new class of cross-reactive invertebrate pan-allergens. Recombinant arginine kinase may be used to identify a group of polysensitized indoor allergic patients and for immunotherapy of these individuals.
Cutting Edge: IL-10-Producing CD4+ T Cells Mediate Tumor Rejection
Authors: Segal Benjamin M. , Glass Deborah D. , Shevach Ethan M. 
Published: April 2014

AbstractIL-10 has potent immunosuppressive properties, and IL-10-producing CD4+ Tr1 cells have been characterized as regulators of Th1-mediated immunity. In this study, using a s.c. model of glioma cell growth in mice, we demonstrate that CD4+, but not CD8+, T cells play a critical role in tumor rejection following vaccination with irradiated glioma cells. Surprisingly, glioma-specific CD4+ T cells produce IL-10 but neither IL-4 nor IFN-γ, and glioma rejection is compromised in IL-10−/− hosts. Hence, our findings demonstrate that IL-10-producing CD4+ T cells can manifest antitumor functions and suggest that IL-10 may have proinflammatory effects in disease states.
Human Immature Dendritic Cells Efficiently Bind and Take up Secretory IgA Without the Induction of Maturation
Authors: Heystek Heleen C. , Moulon Corinne , Woltman Andrea M. , Garonne Pierre , van Kooten Cees 
Published: April 2014

Abstract
Immature dendritic cells (DC) reside in peripheral tissues, where they pick up and process incoming pathogens via scavenger receptors or FcR such as FcγR and FcεR. At mucosal surfaces, IgA is the main Ig to protect the body from incoming pathogens. In addition, DC are present in high numbers at these sites. We detected expression of FcαR (CD89) on the CD14+ population of CD34+ progenitor-derived DC and on monocyte-derived DC (MoDC). However, CD89 expression was strongly decreased upon differentiation from monocyte to DC. We found only minimal binding of serum IgA to MoDC but strong binding of secretory IgA (SIgA). The SIgA binding to MoDC could not be blocked by anti-CD89 blocking Abs. DC efficiently internalized SIgA, but not serum IgA, and uptake of SIgA could be blocked by specific sugars or partially by Ab reactive with mannose receptor. Importantly, binding and uptake of SIgA was not accompanied by signs of DC maturation, such as increased expression of CD86 and CD83 or induction of cytokine secretion. These data indicate that SIgA can interact with DC not via CD89, but via carbohydrate-recognizing receptors like mannose receptor and suggest that uptake of SIgA-containing immune complexes by immature DC may be a mechanism to modulate mucosal immune responses.
TCRβ Transmembrane Tyrosines Are Required for Pre-TCR Function
Authors: Spain Lisa M. , Liu Pinghu 
Published: April 2014

AbstractThe pre-TCR promotes thymocyte development in the αβ lineage. Productive rearrangement of the TCRβ locus triggers the assembly of the pre-TCR, which includes the pTα chain and CD3 εγδζ subunits. This complex receptor signals the up-regulation of CD4 and CD8 expression, thymocyte proliferation/survival, and the cessation of TCRβ rearrangements (allelic exclusion). In this study, we investigate the function of two conserved tyrosine residues located in the TCRβ chain transmembrane region of the pre-TCR. We show that replacement of both tyrosines with alanine and expression of the mutant receptor in RAG-1null thymocytes prevents surface expression and abolishes pre-TCR function relative to wild-type receptor. Replacement of both tyrosines with phenylalanines (YF double mutant) generates a complex phenotype in which thymocyte survival and proliferation are severely disrupted, differentiation is moderately disrupted, and allelic exclusion is unaffected. We further show that the YF double mutant receptor is expressed on the cell surface and associates with pTα and CD3ε at the same level as does wild-type TCRβ, while association of the YF double mutant with CD3ζ is slightly reduced relative to wild type. These data demonstrate that pre-TCR signaling pathways leading to proliferation and survival, differentiation, and allelic exclusion are differently sensitive to subtle mutation-induced alterations in pre-TCR structure.
Lactobacilli Differentially Modulate Expression of Cytokines and Maturation Surface Markers in Murine Dendritic Cells
Authors: Christensen Hanne R. , Frøkiær Hanne , Pestka James J. 
Published: April 2014

AbstractDendritic cells (DC) play a pivotal immunoregulatory role in the Th1, Th2, and Th3 cell balance and are present throughout the gastrointestinal tract. Thus, DC may be targets for modulation by gut microbes, including ingested probiotics. In the present study, we tested the hypothesis that species of Lactobacillus, important members of the gut flora, differentially activate DC. Bone marrow-derived murine DC were exposed to various lethally irradiated Lactobacillus spp. and resultant culture supernatants were analyzed for IL-6, IL-10, IL-12, and TNF-α. Substantial differences were found among strains in the capacity to induce IL-12 and TNF-α production in the DC. Similar but less pronounced differences were observed among lactobacilli in the induction of IL-6 and IL-10. Although all strains up-regulated surface MHC class II and B7-2 (CD86), which is indicative of DC maturation, those lactobacilli with greatest capacity to induce IL-12 were most effective. Remarkably, Lactobacillus reuteri DSM12246, a poor IL-12 inducer, inhibited IL-12, IL-6, and TNF-α induction by the otherwise strong cytokine inducer L. casei CHCC3139, while IL-10 production remained unaltered. In analogous fashion, L. reuteri reduced L. casei-induced up-regulation of B7-2. These results suggest that different species of Lactobacillus exert very different DC activation patterns and, furthermore, at least one species may be capable of inhibiting activities of other species in the genus. Thus, the potential exists for Th1/Th2/Th3-driving capacities of the gut DC to be modulated according to composition of gut microflora, including ingested probiotics.
Chronic Soluble Antigen Sensitization Primes a Unique Memory/Effector T Cell Repertoire Associated with Th2 Phenotype Acquisition In Vivo
Authors: Foucras Gilles , Gallard Alexandra , Coureau Christiane , Kanellopoulos Jean-M. , Guéry Jean-Charles 
Published: April 2014

AbstractAlthough much progress has been made in characterization of the signaling pathways that control Th cell commitment, little is known about the early events that govern differentiation of IL-4-producing T lymphocytes in vivo. We have previously shown that chronic administration of low dose, soluble hen egg white lysozyme (HEL) induced the selective development of Ag-specific Th2 in genetically predisposed BALB/c mice. Here, we show that these memory/effector Th2 cells express a unique TCR Vβ repertoire, different from the TCR Vβ profile of primary effector cells from HEL-adjuvant-primed mice. This Th2-associated repertoire contains a highly frequent public clonotype characterized by preferred TCR AV and BV gene segment usage along with conserved sequences in the third hypervariable regions of both TCR chains. This Th2 clonotype, which is not recruited in primary effector T cells from HEL-adjuvant-immunized mice, recognized an IAd-restricted HEL determinant, preferentially processed by dendritic cells, but not by B cells. Thus, IL-4-producing CD4 T cells that expand following chronic Ag sensitization emerge from a distinct pool of precursors, supporting the hypothesis that ligand-TCR interactions play a crucial role in the regulation of Ag-specific Th2 cell development in vivo.
Elevated NF-κB Activation in Nonobese Diabetic Mouse Dendritic Cells Results in Enhanced APC Function
Authors: Poligone Brian , Weaver Donald J. , Sen Pradip , Baldwin Albert S. , Tisch Roland 
Published: April 2014

Abstract
We have recently demonstrated that dendritic cells (DC) prepared from nonobese diabetic (NOD) mice, a spontaneous model for insulin-dependent diabetes mellitus, exhibit elevated levels of NF-κB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-κB activation on the APC function of bone marrow-derived DC prepared from NOD vs BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus were found to be more efficient than BALB/c DC at stimulating in vitro naive Ag-specific CD8+ T cells. The T cell stimulatory capacity of NOD DC was suppressed by gene transfer of a modified form of IκBα, indicating a direct role for NF-κB in this process. Furthermore, neutralization of IL-12(p70) to block autocrine-mediated activation of DC also significantly reduced the capacity of NOD DC to stimulate T cells. Despite a reduction in low molecular mass polypeptide-2 expression relative to BALB/c DC, no effect on proteasome-dependent events associated with the NF-κB signaling pathway or Ag processing was detected in NOD DC. Finally, DC from nonobese diabetes-resistant mice, a strain genotypically similar to NOD yet disease resistant, resembled BALB/c and not NOD DC in terms of the level of NF-κB activation, secretion of IL-12(p70) and TNF-α, and the capacity to stimulate T cells. Therefore, elevated NF-κB activation and enhanced APC function are specific for the NOD genotype and correlate with the progression of insulin-dependent diabetes mellitus. These results also provide further evidence indicating a key role for NF-κB in regulating the APC function of DC.
Contributions from Self-Renewal and Trafficking to the Uterine NK Cell Population of Early Pregnancy
Authors: Chantakru Sirirak , Miller Craig , Roach Lindsay E. , Kuziel William A. , Maeda Nobuyo , Wang Wan-Chao , Evans Sharon S. , Croy B. Anne 
Published: April 2014

AbstractUterine NK (uNK) cells are abundant in human and murine uteri during decidualization. It is unclear whether precursors of uNK (pre-uNK) cells self-renew or are recruited from other sites. To assess self-renewal of pre-uNK cells, uterine segments from NK cell-competent mice were grafted orthotopically into NK/uNK cell-deficient or wild-type mice. Only in wild-type recipients did decidualized grafts contain uNK cells, indicating that pre-uNK cells do not self-renew in uterus. To identify pre-uNK cell sources, thymus, bone marrow, lymph node, or spleen cells were grafted from virgin or pregnant NK cell-competent donors into mated NK/uNK cell-deficient recipients. Cells from secondary lymphoid tissues of pregnant donors gave high level uNK cell reconstitution, which was independent of chemokine receptors CCR2 or CCR5. Pregnancy-induced changes to lymphocyte-endothelial cell interactions were documented using adhesion of human lymphocytes to frozen mouse tissue sections under shear. A dynamic increase was observed in L-selectin- and α4 integrin-dependent adhesion of CD56bright NK cells to decidualizing uterus and in human PBL adhesion to lymph node endothelium. These data support a model that attributes the dramatic increases in human and murine uNK cells during decidualization to precursor cell recruitment.