bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrin αE(CD103)β7 Mediates Adhesion to Intestinal Microvascular Endothelial Cell Lines Via an E-Cadherin-Independent Interaction
Authors: Strauch Ulrike G. , Mueller Ruth C. , Li Xiao Y. , Cernadas Manuela , Higgins Jonathan M. G. , Binion David G. , Parker Christina M. 
Published: April 2014

AbstractIntegrins are important for T cell interactions with endothelial cells. Because the integrin αEβ7 is expressed on some circulating gut-homing T cells and as T cell numbers are reduced in the intestinal lamina propria of αE-deficient mice, we evaluated whether αEβ7 mediates binding to intestinal endothelial cells. We found that anti-αEβ7 mAbs partially blocked the binding of cultured intraepithelial T cells to human intestinal microvascular endothelial cells (HIMEC). Furthermore, αEβ7-transfected K562 cells bound more efficiently than vector-transfected K562 cells to HIMEC. Finally, HIMEC bound directly to an αEβ7-Fc fusion protein. These interactions were partially blocked by anti-αEβ7 mAbs, and endothelial cell binding to the αEβ7-Fc was dependent upon the metal ion-dependent adhesion site within the αE A domain. Of note, the HIMEC lacked expression of E-cadherin, the only known αEβ7 counterreceptor as assessed by functional studies, flow cytometry, and RT-PCR. Thus, HIMEC/αEβ7 binding was independent of E-cadherin. In addition, this interaction appeared to be tissue selective, as HIMEC bound to the αEβ7-Fc, whereas microvascular endothelial cells from the skin did not. Finally, there was evidence for an αEβ7 ligand on intestinal endothelial cells in vivo, as αEβ7 expression enhanced lymphocyte binding around vessels in the lamina propria in tissue sections. Thus, we have defined a novel interaction for αEβ7 at a nonepithelial location. These studies suggest a role for αEβ7 in interactions with the intestinal endothelium that may have implications for intestinal T cell homing or functional responses.
HLA-DP Allele-Specific T Cell Responses to Beryllium Account for DP-Associated Susceptibility to Chronic Beryllium Disease
Authors: Lombardi Giovanna , Germain Conrad , Uren Julia , Fiorillo Maria Teresa , du Bois Ronald M. , Jones-Williams William , Saltini Cesare , Sorrentino Rosa , Lechler Robert 
Published: April 2014

Abstract
Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in ∼3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DPβ-chain. T cell clones were raised from three patients with CBD in whom exposure occurred 10 and 30 years previously. Of 25 Be-specific clones that were obtained, all were restricted by HLA-DP alleles with Glu at DPβ69. Furthermore, the proliferative responses of the clones were absolutely dependent upon DPβ Glu69 in that a single amino acid substitution at this position abolished the response. As befits a disease whose pathogenesis involves a delayed type hypersensitivity response, the large majority of Be-specific clones secreted IFN-γ (Th1) and little or no IL-4 (Th2) cytokines. This study provides insights into the molecular basis of DP2-associated susceptibility to CBD.
CD40/CD40 Ligand Interactions Are Critical for Elicitation of Autoimmune-Mediated Fibrosis in the Lung
Authors: Zhang-Hoover Jie , Sutton Annika , Stein-Streilein Joan 
Published: April 2014

AbstractPulmonary interstitial fibrosis (PIF), associated with persistent inflammation and increased collagen deposition in the interstitium, is often considered an autoimmune disease. Hapten immune PIF (HIPIF), a model for PIF, is elicited in the lung by a single intratracheal (i.t.) challenge in mice sensitized with hapten (2,4,6-trinitrobenzene sulfonic acid, TNBS). In this study, we characterized the role of CD40/CD40 ligand (CD40L) interactions in the elicitation of secondary cell-mediated immune responses that lead to development of fibrosis in the lung using an adoptive transfer model of HIPIF. The expression of CD40 was detected on bronchoalveolar lavage (BAL) cells 1–3 days after i.t. challenge with hapten in the HIPIF lung, but not lungs from the control mice. The CD40bright BAL cells morphologically resembled infiltrating monocytes. Furthermore, blocking CD40/CD40L interactions with blocking Ab decreased BAL production of Th1-mediators (IL-12 and TNF-α). Moreover, either blocking CD40/CD40L interactions with the Ab or using IL-12 knockout recipient mice prevented the increased collagen deposition (accumulation of hydroxyproline) in the lungs during HIPIF induction. We conclude that second signals (CD40/CD40L interactions) are required for elicitation of secondary immune responses that lead to PIF in vivo. The results support the notion that CD40/CD40L interactions are involved in the pathogenesis of an ongoing autoimmune disease.
Gene Expression of Osteoclast Differentiation Factor Is Induced by Lipopolysaccharide in Mouse Osteoblasts Via Toll-Like Receptors
Authors: Kikuchi Takeshi , Matsuguchi Tetsuya , Tsuboi Naotake , Mitani Akio , Tanaka Shigehisa , Matsuoka Masanori , Yamamoto Genta , Hishikawa Toshimitsu , Noguchi Toshihide , Yoshikai Yasunobu 
Published: April 2014

AbstractOsteoclast differentiation factor (ODF), a recently identified cytokine of the TNF family, is expressed as a membrane-associated protein in osteoblasts and stromal cells. ODF stimulates the differentiation of osteoclast precursors into osteoclasts in the presence of M-CSF. Here we investigated the effects of LPS on the gene expression of ODF in mouse osteoblasts and an osteoblast cell line and found that LPS increased the ODF mRNA level. A specific inhibitor of extracellular signal-regulated kinase or protein kinase C inhibited this up-regulation, indicating that extracellular signal-regulated kinase and protein kinase C activation was involved. A protein synthesis inhibitor, cycloheximide, rather enhanced the LPS-mediated increase of ODF mRNA, and both a neutralizing Ab of TNF-α and a specific inhibitor of PGE synthesis failed to block the ODF mRNA increase by native LPS. Thus, LPS directly induced ODF mRNA. Mouse osteoblasts and an osteoblast cell line constitutively expressed Toll-like receptor (TLR) 2 and 4, which are known as putative LPS receptors. ODF mRNA increases in response to synthetic lipid A were defective in primary osteoblasts from C3H/HeJ mice that contain a nonfunctional mutation in the TLR4 gene, suggesting that TLR4 plays an essential role in the process. Altogether, our results indicate that ODF gene expression is directly increased in osteoblasts by LPS treatment via TLR, and this pathway may play an important role in the pathogenesis of LPS-mediated bone disorders, such as periodontitis.
IC14, an Anti-CD14 Antibody, Inhibits Endotoxin-Mediated Symptoms and Inflammatory Responses in Humans
Authors: Verbon Annelies , Dekkers Pascale E. P. , ten Hove Tessa , Hack C. Erik , Pribble John P. , Turner Terence , Souza Sonia , Axtelle Tim , Hoek Frans J. , van Deventer Sander J. H. , van der Poll Tom 
Published: April 2014

AbstractCD14 is a receptor for cell wall components of Gram-negative and Gram-positive bacteria that has been implicated in the initiation of the inflammatory response to sepsis. To determine the role of CD14 in LPS-induced effects in humans, 16 healthy subjects received an i.v. injection of LPS (4 ng/kg) preceded (−2 h) by i.v. IC14, a recombinant chimeric mAb against human CD14, at a dose of 1 mg/kg over 1 h, or placebo. In subjects receiving IC14, saturation of CD14 on circulating monocytes and granulocytes was &gt;90% at the time of LPS injection. IC14 attenuated LPS-induced clinical symptoms and strongly inhibited LPS-induced proinflammatory cytokine release, while only delaying the release of the anti-inflammatory cytokines soluble TNF receptor type I and IL-1 receptor antagonist. IC14 also inhibited leukocyte activation, but more modestly reduced endothelial cell activation and the acute phase protein response. The capacity of circulating monocytes and granulocytes to phagocytose Escherichia coli was only marginally reduced after infusion of IC14. These data provide the first proof of principle that blockade of CD14 is associated with reduced LPS responsiveness in humans in vivo.
Antigen-Independent Suppression of the Allergic Immune Response to Bee Venom Phospholipase A2 by DNA Vaccination in CBA/J Mice
Authors: Jilek Samantha , Barbey Catherine , Spertini François , Corthésy Blaise 
Published: April 2014

AbstractPhospholipase A2 (PLA2) is one of the major honey bee venom allergens for humans. To assess the long-term prevention of allergic reactions by DNA vaccination, a PLA2-CBA/J mouse model was employed using empty or PLA2 sequence-carrying DNA plasmids. Early skin application of either DNA construct before (prophylactic approach) or after (therapeutic approach) sensitization with PLA2/alum led to reduced PLA2-specific IgE and IgG1 titers at 7 mo, with concomitant rise in IgG2a and IgG3. Splenocytes recovered at 5–6 mo after the last DNA administration exhibited a sustained IFN-γ and IL-10 secretion and reduced IL-4 production. Recall challenge with PLA2 boosted IFN-γ and IL-10 secretion, suggesting the reactivation of quiescent memory Th1 lymphocytes. Mice from the prophylactic groups were fully protected against anaphylaxis, whereas 65% of the animals recovered in the therapeutic groups. Th1-polarized immune responses were also active in mice vaccinated with an empty plasmid 32 wk before sensitization with another Ag (OVA). This is the first demonstration that the Ag-coding sequence in DNA vaccine is not necessary to promote immune modulation in naive and sensitized animals for a prolonged period, and has relevance for the understanding of the innate and induced mechanisms underlying gene immunotherapy in long-term treatment of allergy.
Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions
Authors: Corinti Silvia , Albanesi Cristina , la Sala Andrea , Pastore Saveria , Girolomoni Giampiero 
Published: April 2014

AbstractIL-10 is a critical cytokine that blocks the maturation of dendritic cells (DCs), but the relevance of autocrine IL-10 on DC functions has not been investigated. In this study, we found that immature monocyte-derived DCs released low but sizeable amounts of IL-10. After stimulation with bacteria, LPS, lipoteichoic acid, or soluble CD40 ligand, DCs secreted high levels of IL-10. Addition of an anti-IL-10-neutralizing Ab to immature DCs as well as to soluble CD40 ligand- or LPS-maturing DCs led to enhanced expression of surface CD83, CD80, CD86, and MHC molecules and markedly augmented release of TNF-α and IL-12, but diminished IL-10 mRNA expression. Moreover, DCs treated with anti-IL-10 Ab showed an increased capacity to activate allogeneic T cells and primed naive T cells to a more prominent Th1 polarization. DC maturation and IL-10 neutralization were associated with enhanced accumulation of the IL-10 receptor binding chain (IL-10R1) mRNA and intracellular IL-10R1 protein. In contrast, surface IL-10R1 and IL-10 binding activity diminished in mature DCs. These results indicate that autocrine IL-10 prevents spontaneous maturation of DCs in vitro, limits LPS- and CD40-mediated maturation, and increases IL-10 production by DCs. Moreover, IL-10R expression appears to be regulated by both transcriptional and posttranscriptional mechanisms. Endogenous IL-10 and IL-10R can be relevant targets for the manipulation of DC functions.
Identification of an IL-2 Binding Protein in the Saliva of the Lyme Disease Vector Tick, Ixodes scapularis
Authors: Gillespie R. Dean , Dolan Marc C. , Piesman Joseph , Titus Richard G. 
Published: April 2014

Abstract
A potent inhibitor of mitogen-stimulated T cell proliferation exists in the saliva of several species of hard ticks, including the Lyme disease vector tick, Ixodes scapularis. Our characterization of this phenomenon has led to the identification of a possible mechanism for the T cell inhibitory activity of I. scapularis saliva. The T cell inhibitor can overcome stimulation of mouse spleen cells with anti-CD3 mAb; however, a direct and avid interaction with T cells does not appear to be necessary. Tick saliva inhibits a mouse IL-2 capture ELISA, suggesting that a soluble IL-2 binding factor is present in the saliva. This hypothesis was verified by using a direct binding assay in which plate-immobilized tick saliva was shown to bind both mouse and human IL-2. Elimination of the IL-2 binding capacity of saliva in the in vitro assays by trypsin digestion demonstrated that the IL-2 binding factor is a protein. These experiments comprise the first demonstration of the existence of such a secreted IL-2 binding protein from any parasite or pathogen. This arthropod salivary IL-2 binding capacity provides a simple mechanism for the suppression of T cell proliferation as well as for the activity of other immune effector cells that are responsive to IL-2 stimulation. Relevance of the tick T cell inhibitory activity to the human immune system is demonstrated by the ability of tick saliva to inhibit proliferation of human T cells and CTLL-2 cells grown in the presence of human IL-2.
Biological Activity of Soluble CD100. II. Soluble CD100, Similarly to H-SemaIII, Inhibits Immune Cell Migration
Authors: Delaire Stéphanie , Billard Christian , Tordjman Rafaèle , Chédotal Alain , Elhabazi Abdellah , Bensussan Armand , Boumsell Laurence 
Published: April 2014

AbstractCD100 is a human 150-kDa homodimer expressed at the surface of most hemopoietic cells, and its gene belongs to the Ig and semaphorin gene families. Semaphorin genes encode soluble and membrane-bound proteins, most of which have been shown to act as chemorepellents on growth cone guidance. CD100 is discrete, as it is a transmembrane leukocyte surface molecule that can also exist in a soluble form. While our previous studies using mAbs suggested that the transmembrane form of CD100 plays a role in lymphocyte activation, no function was shown for its soluble form. Here, we investigated the effect of soluble CD100 in a cell migration assay; both CD100 spontaneously shed from a stable transfectant and soluble recombinant CD100 inhibited spontaneous and chemokine-induced migration of human monocytes. Interestingly, only the dimeric form of CD100 exerted an effect. Moreover, soluble CD100 inhibited migration of cells from monocytic and B cell lineages. A similar inhibitory effect on migration was observed with H-SemaIII, but not H-SemaIV, semaphorins. In addition, both CD100 and H-SemaIII were recognized by two CD100 mAbs in an ELISA, and one of these mAb abolished the inhibitory effect of each of these semaphorins. We also provide evidence that CD100 and H-SemaIII act through the same receptor on immune cells, which is not neuropilin-1. Furthermore, we describe a function on immune cells for H-SemaIII, a semaphorin to date only studied in the nervous system.
IL-9 and IL-13 Production by Activated Mast Cells Is Strongly Enhanced in the Presence of Lipopolysaccharide: NF-κB Is Decisively Involved in the Expression of IL-9
Authors: Stassen Michael , Müller Christian , Arnold Martina , Hültner Lothar , Klein-Hessling Stefan , Neudörfl Christine , Reineke Tanja , Serfling Edgar , Schmitt Edgar 
Published: April 2014

Abstract
Mast cells, due to their ability to produce a large panel of mediators and cytokines, participate in a variety of processes in adaptive and innate immunity. Herein we report that in primary murine bone marrow-derived mast cells activated with ionomycin or IgE-Ag the bacterial endotoxin LPS strongly enhances the expression of IL-9 and IL-13, but not IL-4. This costimulatory effect of LPS is absent in activated mast cells derived from the LPS-hyporesponsive mouse strain BALB/c-LPSd, although in these cells the proinflammatory cytokine IL-1 can still substitute for LPS. The enhanced production of mast cell-derived IL-13 in the presence of IL-1 is a novel observation. Coactivation of mast cells with LPS leads to a synergistic activation of NF-κB, which is shown by an NF-κB-driven reporter gene construct. In the presence of an inhibitor of NF-κB activation, the production of IL-9 is strongly decreased, whereas the expression of IL-13 is hardly reduced, and that of IL-4 is not affected at all. NF-κB drives the expression of IL-9 via three NF-κB binding sites within the IL-9 promoter, which we characterize using gel shift analyses and reporter gene assays. In the light of recent reports that strongly support critical roles for IL-9 and IL-13 in allergic lung inflammation, our results emphasize the potential clinical importance of LPS as an enhancer of mast cell-derived IL-9 and IL-13 production in the course of inflammatory reactions and allergic diseases.
Regulation of Activator Protein-1 and NF-κB in CD8+ T Cells Exposed To Peripheral Self-Antigens
Authors: Guerder Sylvie , Rincòn Mercedes , Schmitt-Verhulst Anne-Marie 
Published: April 2014

Abstract
The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown. In this study, we analyzed the regulation of AP-1- and NF-κB-mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes. Naive CD8+Désiré (Des)+ T cells isolated from the Des TCR-transgenic mice that are specific for the H-2Kb class I Ag were transferred into Alb-Kb-transgenic mice that express the H-2Kb Ag on hepatocytes only. Tolerance develops in these mice. We found that the self-reactive CD8+Des+ T cells were transiently activated, then became unresponsive and were further deleted. In contrast to CD8+Des+ T cells activated in vivo with APCs, which express high AP-1 and high NF-κB transcriptional activity, the unresponsive CD8+Des+ T cells expressed no AP-1 and only weak NF-κB transcriptional activity. The differences in NF-κB transcriptional activity correlated with the generation of distinct NF-κB complexes. Indeed, in vivo primed T cells predominantly express p50/p50 and p65/p50 dimers, whereas these p50-containing complexes are barely detectable in tolerant T cells that express p65- and c-Rel-containing complexes. These observations suggest that fine regulation of NF-κB complex formation may determine T cell fate.
A Role for Accessibility to Self-Peptide-Self-MHC Complexes in Intrathymic Negative Selection
Authors: Viret Christophe , Sant’Angelo Derek B. , He Xin , Ramaswamy Hemavathi , Janeway Charles A. 
Published: April 2014

Abstract
Whether intrathymic-positive and -negative selection of conventional αβ T cells occur in anatomically distinct sites is a matter of debate. By using a system composed of two distinct immune receptors, the Y-Ae mAb and the 1H3.1 (Vα1/Vβ6) TCR, both directed against the 52–68 fragment of the I-Eα-chain (Eα52–68) bound to I-Ab, we examined the occurrence of negative selection imposed in vivo by a self-peptide-self-MHC class II complex with differential tissue expression. 1H3.1 TCR-transgenic (Tg) mice were bred to mice having an I-Eα transgene with expression directed to all MHC class II-positive cells, restricted to thymic epithelial cells, or restricted to B cells, dendritic cells, and medullary thymic epithelial cells. All 1H3.1 TCR/I-Eα double-Tg mice revealed a severely diminished thymic cellularity. Their lymph node cells were depleted of Vβ6+CD4+ cells and were unresponsive to Eα52–68 in vitro. The absolute number of CD4+CD8+ thymocytes was drastically reduced in all combinations, indicating that negative selection caused by an endogenously expressed self-determinant can effectively occur in the thymic cortex in vivo. Moreover, both cortical epithelial cells and, interestingly, the few cortical dendritic cells were able to support negative selection of CD4+CD8+ thymocytes, albeit with a distinct efficiency. Collectively, these observations support a model where, in addition to the avidity of the thymocyte/stromal cell interaction, in vivo negative selection of autoreactive TCR-Tg T cells is determined by accessibility to self-peptide-self-MHC complexes regardless of the anatomical site.
Distinguishing Self from Nonself: Immunogenicity of the MurineH47Locus Is Determined by a Single Amino Acid Substitution in an Unusual Peptide
Authors: Mendoza Lisa M. , Villaflor Gilbert , Eden Peter , Roopenian Derry , Shastri Nilabh 
Published: April 2014

AbstractHistocompatibility (H) Ags are responsible for chronic graft rejection and graft vs host disease in solid tissue and bone marrow transplantation among MHC-matched individuals. Here we defined the molecular basis of self-nonself discrimination for the murine chromosome 7 encoded H47 histocompatibility locus, known by its trait of graft-rejection for over 40 years. H47 encodes a novel, highly conserved cell surface protein containing the SCILLYIVI (SII9) nonapeptide in its transmembrane region. The p7 isoleucine-to-phenylalanine substitution in SII9 defined the antigenic polymorphism and T cell specificity. Despite absence of the canonical consensus motif and weak binding to Db MHC I, both H47 peptides were presented to CTLs. However, unlike all the other known H loci, the relative immunogenicity of both H47 alleles varied dramatically and was profoundly influenced by neighboring H loci. The results provide insights into the peptide universe that defines nonself and the basis of histoincompatibility.
Inducible Expression of Stat4 in Dendritic Cells and Macrophages and Its Critical Role in Innate and Adaptive Immune Responses
Authors: Fukao Taro , Frucht David M. , Yap George , Gadina Massimo , O’Shea John J. , Koyasu Shigeo 
Published: April 2014

Abstract
Autocrine activation of APC by IL-12 has recently been revealed; we demonstrate here that inducible expression of Stat4 in APC is central to this process. Stat4 is induced in dendritic cells (DC) in a maturation-dependent manner and in macrophages in an activation-dependent manner. Stat4 levels directly correlate with IL-12-dependent IFN-γ production by APC as well as IFN-γ production by DC during Ag presentation. The Th2 cytokines IL-4 and IL-10 suppress Stat4 induction in DC and macrophages when present during maturation and activation, respectively, diminishing IFN-γ production. In contrast, IL-4 has no effect on Stat4 levels in mature DC and actually augments IFN-γ production by DC during Ag presentation, indicating that IL-4 acts differently in a spatiotemporal manner. The functional importance of Stat4 is evident in Stat4−/− DC and macrophages, which fail to produce IFN-γ. Furthermore, Stat4−/− macrophages are defective in NO production in response to IL-12 and are susceptible to Toxoplasma. Autocrine IL-12 signaling is required for high-level IFN-γ production by APC at critical stages in both innate and adaptive immunity, and the control of Stat4 expression is likely an important regulator of this process.
Suppression of IL-12 Transcription in Macrophages Following Fcγ Receptor Ligation
Authors: Grazia Cappiello Maria , Sutterwala Fayyaz S. , Trinchieri Giorgio , Mosser David M. , Ma Xiaojing 
Published: April 2014

Abstract
Ligating FcγR on macrophages results in suppression of IL-12 production. We show that FcγR ligation selectively down-regulates IL-12 p40 and p35 gene expression at the level of transcription. The region responsive to this inhibition maps to the Ets site of the p40 promoter. PU.1, IFN consensus sequence binding protein, and c-Rel form a complex on this element upon macrophage activation. Receptor ligation abolishes the binding of this PU.1-containing activation complex, and abrogates p40 transcription. A dominant-negative construct of PU.1 diminishes IL-12 p40 promoter activity and endogenous IL-12 p40 protein secretion. Thus, the specificity of IL-12 down-regulation following receptor ligation lies in the inhibition of binding of a PU.1-containing complex to the Ets site of the IL-12 promoter. These findings provide evidence demonstrating for the first time the importance of PU.1 in the transcriptional regulation of IL-12 gene expression.