bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of S100A8 and S100A9 Suppresses Neutrophil Migration in Response to Lipopolysaccharide
Authors: Vandal Karen , Rouleau Pascal , Boivin Annie , Ryckman Carle , Talbot Mariève , Tessier Philippe A. 
Published: April 2014

AbstractRecently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils. Passive immunization against S100A8 and S100A9 led to a 52% inhibition of neutrophil migration in response to LPS at 3 h postinjection. Injection of LPS was also associated with an increase in peripheral blood neutrophils and the presence in serum of S100A9 and S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9 augmented the number of circulating neutrophils and diminished the number of neutrophils in the bone marrow, demonstrating that S100A8 and S100A9 induced the mobilization of neutrophils from the bone marrow to the blood. Finally, passive immunization with anti-S100A9 inhibited the neutrophilia associated with LPS injection in the air pouch. These results suggest that S100A8 and S100A9 play a role in the inflammatory response to LPS by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site.
Unique Effect of Arachidonic Acid on Human Neutrophil TNF Receptor Expression: Up-Regulation Involving Protein Kinase C, Extracellular Signal-Regulated Kinase, and Phospholipase A2
Authors: Moghaddami Nahid , Costabile Maurizio , Grover Phulwinder K. , Jersmann Hubertus P. A. , Huang Zhi H. , Hii Charles S. T. , Ferrante Antonio 
Published: April 2014

Abstract
Arachidonic acid (AA) regulates the function of many cell types, including neutrophils. Although much emphasis has been placed on agonist-induced down-regulation of TNFR, our data show that AA caused a rapid (10–20 min) and dose-dependent (0.5–30 μM) increase in the surface expression of both classes of TNFR (TNFR1 and TNFR2) on human neutrophils. This increased TNFR expression correlated with an increase in TNF-induced superoxide production. In contrast, the ω3 fatty acids eicosapentaenoic acid, docosahexaenoic acid, and linolenic acid failed to stimulate TNFR expression. Although fMLP and LPS reduced the neutrophil expression of TNFR, when pretreated with AA, fMLP caused an increase in TNFR expression. Consistent with this result was the finding that AA prevented the fMLP-induced receptor release in neutrophil cultures. AA also caused an increase in TNFR expression in matured HL-60 cells (neutrophil-like cells), but a decrease in nonmatured cells and HUVEC. The AA effects were independent of the lipoxygenase and cyclooxygenase pathways, but dependent on protein kinase C, the extracellular signal-regulated kinases 1 and 2, and cytosolic phospholipase A2. The data demonstrate a unique effect of AA in the inflammatory reaction, through its action on neutrophil TNFR expression, and suggest that AA may regulate the response of neutrophils to TNF by altering its receptor number.
Coevolution of Markers of Innate and Adaptive Immunity in Skin and Peripheral Blood of Patients with Erythema Migrans
Authors: Salazar Juan C. , Pope Constance D. , Sellati Timothy J. , Feder Henry M. , Kiely Thomas G. , Dardick Kenneth R. , Buckman Ronald L. , Moore Meagan W. , Caimano Melissa J. , Pope Jonathan G. , Krause Peter J. , Radolf Justin D. ,   The Lyme Disease Network
Published: April 2014

AbstractWe used multiparameter flow cytometry to characterize leukocyte immunophenotypes and cytokines in skin and peripheral blood of patients with erythema migrans (EM). Dermal leukocytes and cytokines were assessed in fluids aspirated from epidermal suction blisters raised over EM lesions and skin of uninfected controls. Compared with corresponding peripheral blood, EM infiltrates were enriched for T cells, monocytes/macrophages, and dendritic cells (DCs), contained lower proportions of neutrophils, and were virtually devoid of B cells. Enhanced expression of CD14 and HLA-DR by lesional neutrophils and macrophages indicated that these innate effector cells were highly activated. Staining for CD45RO and CD27 revealed that lesional T lymphocytes were predominantly Ag-experienced cells; furthermore, a subset of circulating T cells also appeared to be neosensitized. Lesional DC subsets, CD11c+ (monocytoid) and CD11c− (plasmacytoid), expressed activation/maturation surface markers. Patients with multiple EM lesions had greater symptom scores and higher serum levels of IFN-α, TNF-α, and IL-2 than patients with solitary EM. IL-6 and IFN-γ were the predominant cytokines in EM lesions; however, greater levels of both mediators were detected in blister fluids from patients with isolated EM. Circulating monocytes displayed significant increases in surface expression of Toll-like receptor (TLR)1 and TLR2, while CD11c+ DCs showed increased expression of TLR2 and TLR4; lesional macrophages and CD11c+ and CD11c− DCs exhibited increases in expression of all three TLRs. These results demonstrate that Borrelia burgdorferi triggers innate and adaptive responses during early Lyme disease and emphasize the interdependence of these two arms of the immune response in the efforts of the host to contain spirochetal infection.
Most Highly Exposed Seronegative Men Lack HIV-1-Specific, IFN-γ-Secreting T Cells
Authors: Hladik Florian , Desbien Anthony , Lang Jean , Wang Lei , Ding Yan , Holte Sarah , Wilson Aaron , Xu Younong , Moerbe Micky , Schmechel Steve , McElrath M. Juliana 
Published: April 2014

Abstract
Naturally acquired cellular immunity in individuals who have been exposed to HIV-1 but have remained uninfected may hold clues for the design of an effective HIV vaccine. To determine the presence and nature of such an HIV-1-specific immune response, we evaluated the quantity and fine specificity of HIV-1-reactive IFN-γ-secreting T cells in a group of highly exposed seronegative men having sex with men. All 46 ES reported frequent unprotected anal sex with known HIV-1-infected partners at enrollment, and high risk activities continued in at least one-half of the volunteers for up to &gt;6 years of observation. Despite the high frequency of unprotected anal intercourse and potential HIV-1 exposure, the vast majority of individuals demonstrated no or very low numbers of HIV-1-specific, IFN-γ-secreting T cells. Even when HIV-1 epitopes were presented by peptide-pulsed autologous dendritic cells in 15 of the highest risk volunteers, HIV-1-specific T cells remained infrequent, and the proportion of responders was not significantly different from that in a lower risk seronegative control cohort. Only PBMC from two individuals who have remained uninfected to date exhibited distinctly positive responses. However, these responses rarely persisted over time, single epitope specificities were identified in only one volunteer, and HIV-1-specific memory T cell clones did not expand in vitro. HIV-1-specific, IFN-γ-secreting T cells are thus unlikely to substantially contribute to resistance against infection in most exposed seronegative men having sex with men.
Genomic Effects of IFN-β in Multiple Sclerosis Patients
Authors: Weinstock-Guttman Bianca , Badgett Darlene , Patrick Kara , Hartrich Laura , Santos Roseane , Hall Dennis , Baier Monika , Feichter Joan , Ramanathan Murali 
Published: April 2014

Abstract
The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-β-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 μg of IFN-β-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for &gt;4000 known genes. IFN-β-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1–4 h of IFN-β treatment. The mRNAs for several genes involved in IFN-β signaling, such as IFN-α/β receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9–27), IFN-induced transmembrane protein 2 (1–8D), β2-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-β treatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy.
Cutting Edge: Diabetes-Associated Quantitative Trait Locus, Idd4, Is Responsible for the IL-12p40 Overexpression Defect in Nonobese Diabetic (NOD) Mice
Authors: Simpson Pedro B. , Mistry Monica S. , Maki Richard A. , Yang Weidong , Schwarz David A. , Johnson Eric B. , Lio Francisco M. , Alleva David G. 
Published: April 2014

Abstract
APCs of the nonobese diabetic (NOD) mouse have a genetically programmed capacity to overexpress IL-12p40, a cytokine critical for development of pathogenic autoreactive Th1 cells. To determine whether a diabetes-associated NOD chromosomal locus (i.e., Idd) was responsible for this defect, LPS-stimulated macrophages from several recombinant congenic inbred mice with Idd loci on a C57BL/6 background or with different combinations of NOD and CBA genomic segments were screened for IL-12p40 production. Only macrophages from the congenic strains containing the Idd4 locus showed IL-12p40 overproduction/expression. Moreover, analysis of IL-12p40 sequence polymorphisms demonstrated that the Idd4 intervals in these strains contained the IL-12p40 allele of the NOD, although further analysis is required to determine whether the IL-12p40 allele itself is responsible for its overexpression. Thus, the non-MHC-associated Idd4 locus appears responsible for IL-12p40 overexpression, which may be a predisposing factor for type 1 diabetes in NOD mice.
Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells
Authors: Tang Qizhi , Henriksen Kammi J. , Boden Elisa K. , Tooley Aaron J. , Ye Jianqin , Subudhi Sumit K. , Zheng Xin X. , Strom Terry B. , Bluestone Jeffrey A. 
Published: April 2014

Abstract
CD28/B7 blockade leads to exacerbated autoimmune disease in the nonobese diabetic mouse strain as a result of a marked reduction in the number of CD4+CD25+ regulatory T cells (Tregs). Herein, we demonstrate that CD28 controls both thymic development and peripheral homeostasis of Tregs. CD28 maintains a stable pool of peripheral Tregs by both supporting their survival and promoting their self-renewal. CD28 engagement promotes survival by regulating IL-2 production by conventional T cells and CD25 expression on Tregs.
Cutting Edge: T Cells from Aged Mice Are Resistant to Depletion Early During Virus Infection
Authors: Jiang Jiu , Anaraki Farvardin , Blank Kenneth J. , Murasko Donna M. 
Published: April 2014

Abstract
Aging is associated with decreased expansion of T cells upon stimulation. In young mice, infection induces a transient T cell depletion followed by the development of an Ag-specific T cell response that controls the infection. We found that T cells were depleted early after infection with E55 + murine leukemia retrovirus in young, but not aged, mice. Adoptive transfer experiments showed donor T cells of young, but not aged, mice were depleted due to apoptosis in various tissues of young recipients. However, T cells of neither young nor aged donors were depleted in aged recipients. These results indicate that both environmental and intrinsic cellular properties limit depletion of T cells of aged mice and suggest a novel explanation for the decreased T cell response associated with aging.
Extrathymic TCR Gene Rearrangement in Human Small Intestine: Identification of New Splice Forms of Recombination Activating Gene-1 mRNA with Selective Tissue Expression
Authors: Bas Anna , Hammarström Sten G. , Hammarström Marie-Louise K. C. 
Published: April 2014

AbstractTwo new 5′-untranslated region (5′UTR) exons were identified in the human gene for the lymphocyte-specific endonuclease recombination activating gene-1 (RAG1) required for the somatic recombination yielding functional Ag receptors. These 5′UTR exons were used in three different splice forms by jejunal lymphocytes of the T cell lineage. RAG1 mRNA containing the previously described 5′UTR exon was not expressed in these cells. Conversely, one of the new 5′UTR exons was not expressed in thymus. The new RAG1 mRNA splice forms were all expressed in immature T cells (CD2+CD7+CD3−). This cell population also expressed high levels of mRNA for the pre-T α-chain. In situ hybridization demonstrated jejunal cells expressing the new splice forms of RAG1 mRNA, both intraepithelially and in lamina propria. Pre-T α-chain mRNA-expressing cells were detected at the same sites. These results strongly suggest ongoing TCR gene rearrangement in human small intestinal mucosa, yielding T cells specially adapted for this environment. This seems to be achieved by two parallel processes, extrathymic T cell development and peripheral Ag-driven TCR editing.
Airway Eosinophils Accumulate in the Mediastinal Lymph Nodes but Lack Antigen-Presenting Potential for Naive T Cells
Authors: van Rijt Leonie S. , Vos Nanda , Hijdra Daniëlle , de Vries Victor C. , Hoogsteden Henk C. , Lambrecht Bart N. 
Published: April 2014

Abstract
Asthma is characterized by infiltration of the airway wall with eosinophils. Although eosinophils are considered to be effector cells, recent studies have reported their ability to activate primed Th2 cells. In this study, we investigated whether eosinophils are capable of presenting Ag to unprimed T cells in draining lymph nodes (DLN) of the lung and compared this capacity with professional dendritic cells (DC). During development of eosinophilic airway inflammation in OVA-sensitized and challenged mice, CCR3+ eosinophils accumulated in the DLN. To study their function, eosinophils were isolated from the bronchoalveolar lavage fluid of mice by sorting on CCR3+B220−CD3−CD11cdim low autofluorescent cells, avoiding contamination with other APCs, and were intratracheally injected into mice that previously received CFSE-labeled OVA TCR-transgenic T cells. Eosinophils did not induce divisions of T cells in the DLN, whereas DC induced on average 3.7 divisions in 45.7% of T cells. To circumvent the need for Ag processing or migration in vivo, eosinophils were pulsed with OVA peptide and were still not able to induce T cell priming in vitro, whereas DC induced vigorous proliferation. This lack of Ag-presenting ability was explained by the very weak expression of MHC class II on fresh eosinophils, despite expression of the costimulatory molecules CD80 and ICAM-1. This investigation does not support any role for airway eosinophils as APCs to naive T cells, despite their migration to the DLN at times of allergen exposure. DC are clearly superior in activating T cells in the DLN of the lung.
Veto-Like Activity of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses to Alloantigens and Recall Antigens
Authors: Potian Julius A. , Aviv Hana , Ponzio Nicholas M. , Harrison Jonathan S. , Rameshwar Pranela 
Published: April 2014

Abstract
Trans-differentiation of stem cells shows promise for use in tissue repair medicine. Although poorly defined, mesenchymal stem cells (MSC) appear useful for applications in repair medicine. Despite the low frequency of MSC, they are relatively easy to expand. The expression of MHC class II on MSC, however, could deter their use in repair medicine, since these molecules could stimulate an allogeneic host response. This study sought to compare the immune stimulatory and suppressive effects of MSC. Primary human MSC were cultured from bone marrow aspirates and then passaged at least three times before use in assays. Morphologically, MSC were symmetrical; were SH2+, MHC class II+, CD45−, CD44+, CD31−, CD14−, proly-4-hydroxylase−; and showed normal karyotype patterns and elevated telomerase activities. MSC elicited significant stimulatory responses when cocultured with allogeneic PBMC. Despite the production of different types of growth factors, allogeneic effects of MSC could not be explained by the production of these growth factors. One-way MLR reactions were significantly blunted by third-party MSC. Similar suppression was not observed for responses to three different recall Ags. Based on these functional differences by MSC in responses to allo- and recall Ags, we examined whether MSC could exert veto-like functions. We showed that MSC could blunt the cytotoxic effects of allogeneic-induced effectors to mitogen-activated targets. The results showed that although MSC elicited allogeneic responses in a model that mimics a graft-vs-host reaction, they also exerted veto-like activity, but caused no effect on responses to recall Ags.
IL-2-Activated CD8+CD44high Cells Express Both Adaptive and Innate Immune System Receptors and Demonstrate Specificity for Syngeneic Tumor Cells
Authors: Dhanji Salim , Teh Hung-Sia 
Published: April 2014

Abstract
CD8+ T cells depend on the αβ TCR for Ag recognition and function. However, Ag-activated CD8+ T cells can also express receptors of the innate immune system. In this study, we examined the expression of NK receptors on a population of CD8+ T cells expressing high levels of CD44 (CD8+CD44high cells) from normal mice. These cells are distinct from conventional memory CD8+ T cells and they proliferate and become activated in response to IL 2 via a CD48/CD2-dependent mechanism. Before activation, they express low or undetectable levels of NK receptors but upon activation with IL-2 they expressed significant levels of activating NK receptors including 2B4 and NKG2D. Interestingly, the IL-2-activated cells demonstrate a preference in the killing of syngeneic tumor cells. This killing of syngeneic tumor cells was greatly enhanced by the expression of the NKG2D ligand Rae-1 on the target cell. In contrast to conventional CD8+ T cells, IL-2-activated CD8+CD44high cells express DAP12, an adaptor molecule that is normally expressed in activated NK cells. These observations indicate that activated CD8+CD44high cells express receptors of both the adaptive and innate immune system and may play a unique role in the surveillance of host cells that have been altered by infection or transformation.
Neuropeptide Y (NPY) Suppresses Experimental Autoimmune Encephalomyelitis: NPY1 Receptor-Specific Inhibition of Autoreactive Th1 Responses In Vivo
Authors: Bedoui Sammy , Miyake Sachiko , Lin Youwei , Miyamoto Katsuichi , Oki Shinji , Kawamura Noriyuki , Beck-Sickinger Annette , von Hörsten Stephan , Yamamura Takashi 
Published: April 2014

Abstract
Prior studies have revealed that the sympathetic nervous system regulates the clinical and pathological manifestations of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model mediated by Th1 T cells. Although the regulatory role of catecholamines has been indicated in the previous works, it remained possible that other sympathetic neurotransmitters like neuropeptide Y (NPY) may also be involved in the regulation of EAE. Here we examined the effect of NPY and NPY receptor subtype-specific compounds on EAE, actively induced with myelin oligodendrocyte glycoprotein 35–55 in C57BL/6 mice. Our results revealed that exogenous NPY as well as NPY Y1 receptor agonists significantly inhibited the induction of EAE, whereas a Y5 receptor agonist or a combined treatment of NPY with a Y1 receptor antagonist did not inhibit signs of EAE. These results indicate that the suppression of EAE by NPY is mediated via Y1 receptors. Furthermore, treatment with the Y1 receptor antagonist induced a significantly earlier onset of EAE, indicating a protective role of endogenous NPY in the induction phase of EAE. We also revealed a significant inhibition of myelin oligodendrocyte glycoprotein 35–55-specific Th1 response as well as a Th2 bias of the autoimmune T cells in mice treated with the Y1 receptor agonist. Ex vivo analysis further demonstrated that autoimmune T cells are directly affected by NPY via Y1 receptors. Taken together, we conclude that NPY is a potent immunomodulator involved in the regulation of the Th1-mediated autoimmune disease EAE.
Diversity of Clonal T Cell Proliferation Is Mediated by Differential Expression of CD152 (CTLA-4) on the Cell Surface of Activated Individual T Lymphocytes
Authors: Maszyna Frank , Hoff Holger , Kunkel Désirée , Radbruch Andreas , Brunner-Weinzierl Monika C. 
Published: April 2014

Abstract
Inhibitory effects of CD152 (CTLA-4) engagement during T cell activation have been described. To date, such effects could only be correlated to CD152 expression at the population level because expression of CD152 on the cell surface is too low to be assessed by conventional immunofluorescence on the single cell level. In this study, we use magnetofluorescent liposomes for the immunofluorescent detection of surface CD152-expressing CD4+ T cells and show that, despite the fact that nearly all cells express intracellular CD152, only a fraction of 12% of activated T cells expresses surface CD152 at any given time point. Surface CD152+ T cells appear with similar kinetics after primary or secondary activation in vitro. However, the frequency of surface CD152+ T cells 48 h postactivation is 2-fold higher during secondary activation. Surface expression of CD152 is independent of the proliferative history of an activated T cell. Instruction of T cells for surface expression of CD152 rather depends on the time elapsed since the onset of activation, with a maximum at 48 h, and requires less than 12 h of Ag exposure. CD152− T cells, when isolated by cell sorting and restimulated, continue to proliferate. CD152 blockade has no effect on their proliferation. Isolated surface CD152+ T cells do not proliferate upon restimulation unless CD152 is blocked. CD152 thus acts directly and autonomously on individual activated and proliferating T lymphocytes. Due to its heterogeneous expression on the cell surface of activated Th cells, CD152 might diversify the T cell response.
Opposing Signals from Pathogen-Associated Molecular Patterns and IL-10 Are Critical for Optimal Dendritic Cell Induction of In Vivo Humoral Immunity to Streptococcus pneumoniae
Authors: Colino Jesus , Snapper Clifford M. 
Published: April 2014

Abstract
Interleukin10 is widely regarded as an inhibitor of immunity in part through its ability to inhibit dendritic cell (DC) function. The present study suggests a modification of this view by demonstrating instead that a critical balance exists between signals mediated by pathogen-associated molecular patterns and IL-10 for optimization of DC induction of an in vivo humoral immune response. Bone marrow-derived, CD8α− DC pulsed with Streptococcus pneumoniae in vitro induce in vivo protein- and polysaccharide-specific Ig isotype responses upon adoptive transfer into naive mice. Following bacterial activation, DC have a limited time during which they can function as effective APCs in vivo due to the onset of maturation-associated apoptosis. Autocrine IL-10, by limiting the time during which DC are responsive to widely varying levels of bacterial stimulation, delays the onset of DC apoptosis and thus prolongs the time during which DC are able to elicit in vivo humoral immunity. These data demonstrate a requirement for properly balanced positive and negative signaling in DC to optimize an in vivo immune response to a pathogen.