bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD56brightCD16− Killer Ig-Like Receptor− NK Cells Display Longer Telomeres and Acquire Features of CD56dim NK Cells upon Activation
Authors: Romagnani Chiara , Juelke Kerstin , Falco Michela , Morandi Barbara , D’Agostino Antonella , Costa Roberta , Ratto Giovanni , Forte Giuseppe , Carrega Paolo , Lui Gabrielle , Conte Romana , Strowig Till , Moretta Alessandro , Münz Christian , Thiel Andreas , Moretta Lorenzo , Ferlazzo Guido 
Published: April 2014

Abstract
Human NK cells can be divided into CD56dimCD16+ killer Ig-like receptors (KIR)+/− and CD56brightCD16− KIR− subsets that have been characterized extensively regarding their different functions, phenotype, and tissue localization. Nonetheless, the developmental relationship between these two NK cell subsets remains controversial. We report that, upon cytokine activation, peripheral blood (PB)-CD56bright NK cells mainly gain the signature of CD56dim NK cells. Remarkably, KIR can be induced not only on CD56bright, but also on CD56dim KIR− NK cells, and their expression correlates with lower proliferative response. In addition, we demonstrate for the first time that PB-CD56dim display shorter telomeres than PB- and lymph node (LN)-derived CD56bright NK cells. Along this line, although human NK cells collected from nonreactive LN display almost no KIR and CD16 expression, NK cells derived from highly reactive LN, efferent lymph, and PB express significant amounts of KIR and CD16, implying that CD56bright NK cells could acquire these molecules in the LN during inflammation and then circulate through the efferent lymph into PB as KIR+CD16+ NK cells. Altogether, our results suggest that CD56brightCD16− KIR− and CD56dimCD16+KIR+/− NK cells correspond to sequential steps of differentiation and support the hypothesis that secondary lymphoid organs can be sites of NK cell final maturation and self-tolerance acquisition during immune reaction.
A Unique Thymic Fibroblast Population Revealed by the Monoclonal Antibody MTS-15
Authors: Gray Daniel H. D. , Tull Dedreia , Ueno Tomoo , Seach Natalie , Classon Brendan J. , Chidgey Ann , McConville Malcolm J. , Boyd Richard L. 
Published: April 2014

AbstractT cell differentiation in the thymus is dependent upon signals from thymic stromal cells. Most studies into the nature of these signals have focused only on the support provided by the thymic epithelium, but there is an emerging view that other stromal cells such as mesenchymal fibroblasts may also be involved. Study of the latter has been hindered by a lack of appropriate markers, particularly those allowing their isolation. In this study, we describe a new surface marker of thymic stroma, MTS-15, and demonstrate its specificity for fibroblasts and a subset of endothelial cells. Coculture experiments showed that the determinant could be transferred between cells. Extensive biochemical analysis demonstrated that the Ag bound by MTS-15 was the glycosphingolipid Forssman determinant, consistent with the distribution observed. Transcriptional analysis of purified MTS-15+ thymic fibroblasts revealed a unique expression profile for a number of chemokines and growth factors important to thymocyte and epithelial cell development. In a model of cyclophosphamide-induced thymic involution and regeneration, fibroblasts were found to expand extensively and express growth factors important to epithelial proliferation and increased T cell production just before thymic regeneration. Overall, this study identifies a useful marker of thymic fibroblasts and highlights this subpopulation as a key player in thymic function by virtue of their support of both thymocytes and epithelial cells.
A Critical Role for p53 in the Control of NF-κB-Dependent Gene Expression in TLR4-Stimulated Dendritic Cells Exposed to Genistein
Authors: Dijsselbloem Nathalie , Goriely Stanislas , Albarani Valentina , Gerlo Sarah , Francoz Sarah , Marine Jean-Christophe , Goldman Michel , Haegeman Guy , Berghe Wim Vanden 
Published: April 2014

Abstract
Considerable research has focused on the anti-inflammatory and antiproliferative activities exhibited by the soy isoflavone genistein. We previously demonstrated that genistein suppresses TNF-α-induced NF-κB-dependent IL-6 gene expression in cancer cells by interfering with the mitogen- and stress-activated protein kinase 1 activation pathway. However, effects of isoflavones on immune cells, such as dendritic cells, remain largely unknown. Here we show that genistein markedly reduces IL-6 cytokine production and transcription in LPS-stimulated human monocyte-derived dendritic cells. More particularly, we observe that genistein inhibits IL-6 gene expression by modulating the transcription factor NF-κB. Examination of NF-κB-related events downstream of TLR4 demonstrates that genistein affects NF-κB subcellular localization and DNA binding, although we observe only a minor inhibitory impact of genistein on the classical LPS-induced signaling steps. Interestingly, we find that genistein significantly increases p53 protein levels. We also show that overexpression of p53 in TLR4/MD2 HEK293T cells blocks LPS-induced NF-κB-dependent gene transcription, indicating the occurrence of functional cross-talk between p53 and NF-κB. Moreover, analysis of IL-6 mRNA levels in bone marrow-derived p53 null vs wild-type dendritic cells confirms a role for p53 in the reduction of NF-κB-dependent gene expression, mediated by genistein.
Genome-Wide Network Analysis Reveals the Global Properties of IFN-β Immediate Transcriptional Effects in Humans
Authors: Fernald Guy Haskin , Knott Simon , Pachner Andrew , Caillier Stacy J. , Narayan Kavitha , Oksenberg Jorge R. , Mousavi Parvin , Baranzini Sergio E. 
Published: April 2014

Abstract
IFN-β effectively controls clinical exacerbations and magnetic resonance imaging activity in most multiple sclerosis patients. However, its mechanism of action has not been yet fully elucidated. In this study we used DNA microarrays to analyze the longitudinal transcriptional profile of blood cells within a week of IFN-β administration. Using differential expression and gene ontology analyses we found evidence of a general decrease in the cellular activity of T lymphocytes resembling the endogenous antiviral response of IFNs. In contrast, most of the differentially expressed genes (DEGs) from untreated individuals were involved in cellular physiological processes. We then used mutual information (MI) to build networks of coregulated genes in both treated and untreated individuals. Interestingly, the connectivity distribution (k) of networks generated with high MI values displayed scale-free properties. Conversely, the observed k for networks generated with suboptimal MI values approximated a Poisson distribution, suggesting that MI captures biologically relevant interactions. Gene networks from individuals treated with IFN-β revealed a tight core of immune- and apoptosis-related genes associated with higher values of MI. In contrast, networks obtained from untreated individuals primarily reflected cellular housekeeping functions. Finally, we trained a neural network to reverse engineer the directionality of the main interactions observed at the biological process level. This is the first study that incorporates network analysis to investigate gene regulation in response to a therapeutic drug in humans. Implications of this method in the creation of personalized models of response to therapy are discussed.
Mannose-Binding Lectin A-Deficient Mice Have Abrogated Antigen-Specific IgM Responses and Increased Susceptibility to a Nematode Infection
Authors: Carter Tim , Sumiya Michiko , Reilly Kerri , Ahmed Rubina , Sobieszczuk Peter , Summerfield John A. , Lawrence Rachel A. 
Published: April 2014

Abstract
To investigate the role of mannose-binding lectin-A (MBL-A) in protection against infectious disease, MBL-A−/−-deficient mice were generated. Using a well-characterized mouse model of human filarial nematode infection, nematode survival and protective immune responses were tested in vivo. Blood-borne Brugia malayi microfilariae survived for significantly longer time periods in MBL-A−/− than in wild-type (WT) mice. However, no differences in either splenic cytokine responses or induction of leukocytes in the blood were observed. A profound abrogation of Ag-specific IgM levels was measured in B. malayi-infected MBL-A−/− mice, and some IgG isotypes were higher than those observed in WT animals. To establish whether there was a defect in Ab responses per se in MBL-A−/− mice or the effect was specific to filarial infection, we immunized these mice with OVA or a carbohydrate-free protein. Significantly, Ag-specific IgM responses were defective to both of these Ags, and Ag-specific IgG responses were largely unaffected. Furthermore, in naive mice, total IgM levels did not differ between MBL-A−/− and WT mice. This article describes the first demonstration that MBL-A may function independently of MBL-C and suggests that MBL-A, like other C-type lectins and members of the complement cascade, is intimately involved in the priming of the humoral Ab response.
Impaired Host Defense in Mice Lacking ONZIN
Authors: Ledford Julie G. , Kovarova Martina , Koller Beverly H. 
Published: April 2014

Abstract
ONZIN is a small, cysteine-rich peptide of unique structure that is conserved in all vertebrates examined to date. We show that ONZIN is expressed at high levels in epithelial cells of the intestinal tract, the lung, and in cells of the immune system including macrophages and granulocytes. Because this pattern of expression is suggestive of a role in innate immune function, we have generated mice lacking this protein and examined their ability to respond to challenge with infectious agents. Onzin−/− mice show a heightened innate immune response after induction of acute peritonitis with Klebsiella pneumoniae. This increased response is consistent with an increased bacterial burden in the Onzin−/− mice. Ex vivo studies show that, whereas phagocytosis is not altered in Onzin−/− neutrophils, phagocytes lacking this protein kill bacteria less effectively. This result identifies ONZIN as a novel class of intracellular protein required for optimal function of the neutrophils after uptake of bacteria.
Role of MyD88 in Route-Dependent Susceptibility to Vesicular Stomatitis Virus Infection
Authors: Zhou Shenghua , Kurt-Jones Evelyn A. , Fitzgerald Katherine A. , Wang Jennifer P. , Cerny Anna M. , Chan Melvin , Finberg Robert W. 
Published: April 2014

Abstract
TLRs are important components of the innate immune response. The role of the TLR signaling pathway in host defense against a natural viral infection has been largely unexplored. We found that mice lacking MyD88, an essential adaptor protein in TLR signaling pathway, were extremely sensitive to intranasal infection with vesicular stomatitis virus, and this susceptibility was dose dependent. We demonstrated that this increased susceptibility correlates with the impaired production of IFN-α and defective induction and maintenance of neutralizing Ab. These studies outline the important role of the TLR signaling pathway in nasal mucosae-respiratory tracts-neuroepithelium environment in the protection against microbial pathogen infections. We believe that these results explain how the route of infection, probably by virtue of activating different cell populations, can lead to entirely different outcomes of infection based on the underlying genetics of the host.
Dynamic Relationship between IFN-γ and IL-2 Profile of Mycobacterium tuberculosis-Specific T Cells and Antigen Load
Authors: Millington Kerry A. , Innes John A. , Hackforth Sarah , Hinks Timothy S. C. , Deeks Jonathan J. , Dosanjh Davinder P. S. , Guyot-Revol Valerie , Gunatheesan Rubamalaar , Klenerman Paul , Lalvani Ajit 
Published: April 2014

Abstract
Distinct IFN-γ and IL-2 profiles of Ag-specific CD4+ T cells have recently been associated with different clinical disease states and Ag loads in viral infections. We assessed the kinetics and functional profile of Mycobacterium tuberculosis Ag-specific T cells secreting IFN-γ and IL-2 in 23 patients with untreated active tuberculosis when bacterial and Ag loads are high and after curative treatment, when Ag load is reduced. The frequencies of M. tuberculosis Ag-specific IFN-γ-secreting T cells declined during 28 mo of follow-up with an average percentage decline of 5.8% per year (p = 0.005), while the frequencies of Ag-specific IL-2-secreting T cells increased during treatment (p = 0.02). These contrasting dynamics for the two cytokines led to a progressive convergence of the frequencies of IFN-γ- and IL-2-secreting cells over 28 mo. Simultaneous measurement of IFN-γ and IL-2 secretion at the single-cell level revealed a codominance of IFN-γ-only secreting and IFN-γ/IL-2 dual secreting CD4+ T cells in active disease that shifted to dominance of IFN-γ/IL-2-secreting CD4+ T cells and newly detectable IL-2-only secreting CD4+ T cells during and after treatment. These distinct T cell functional signatures before and after treatment suggest a novel immunological marker of mycobacterial load and clinical status in tuberculosis that now requires validation in larger prospective studies.
Aluminum Hydroxide Adjuvants Activate Caspase-1 and Induce IL-1β and IL-18 Release
Authors: Li Hanfen , Nookala Suba , Re Fabio 
Published: April 2014

AbstractAluminum hydroxide (Alum) is the only adjuvant approved for routine use in humans, although the basis for its adjuvanticity remains poorly understood. In this study, we show that Alum activates caspase-1 and induce secretion of mature IL-1β and IL-18. Human PBMC or dendritic cells stimulated with pure TLR4 and TLR2 agonists released only traces of IL-1β or IL-18, despite the fact that the IL-1β mRNA was readily induced by both TLR agonists. In contrast, cells costimulated with TLR agonists plus Alum released large amount of IL-1β and IL-18. Alum-induced IL-1β and IL-18 production was not due to enhancement of TLR signaling but rather reflected caspase-1 activation and in mouse dendritic cells occurred in a MyD88-independent fashion. Secretion of other proinflammatory cytokines such as IL-8 was not affected by Alum treatments. However, TLR-induced production of IL-10 was increased and that of IFN-γ-inducible protein decreased by Alum cotreatment. Considering the immunostimulatory activities of these cytokines and the ability of IL-1β to act as adjuvant, our results suggest a mechanism for the adjuvanticity of Alum.
Inflammatory Reactive Oxygen Species-Mediated Hemopoietic Suppression in Fancc-Deficient Mice
Authors: Sejas Daniel P. , Rani Reena , Qiu Yuhui , Zhang Xiaoling , Fagerlie Sara R. , Nakano Hiroyasu , Williams David A. , Pang Qishen 
Published: April 2014

Abstract
Patients with the genomic instability syndrome Fanconi anemia (FA) commonly develop progressive bone marrow (BM) failure and have a high risk of cancer. Certain manifestations of the disease suggest that the FA immune system is dysfunctional and may contribute to the pathogenesis of both BM failure and malignancies. In this study, we have investigated inflammation and innate immunity in FA hemopoietic cells using mice deficient in Fanconi complementation group C gene (Fancc). We demonstrate that Fancc-deficient mice exhibit enhanced inflammatory response and are hypersensitive to LPS-induced septic shock as a result of hemopoietic suppression. This exacerbated inflammatory phenotype is intrinsic to the hemopoietic system and can be corrected by the re-expression of a wild-type FANCC gene, suggesting a potential role of the FANCC protein in innate immunity. LPS-mediated hemopoietic suppression requires two major inflammatory agents, TNF-α and reactive oxygen species. In addition, LPS-induced excessive accumulation of reactive oxygen species in Fancc−/− BM cells overactivates the stress kinase p38 and requires prolonged activation of the JNK. Our data implicate a role of inflammation in pathogenesis of FA and BM failure diseases in general.
Scar-Associated Macrophages Are a Major Source of Hepatic Matrix Metalloproteinase-13 and Facilitate the Resolution of Murine Hepatic Fibrosis
Authors: Fallowfield Jonathan A. , Mizuno Masashi , Kendall Timothy J. , Constandinou Christothea M. , Benyon R. Christopher , Duffield Jeremy S. , Iredale John P. 
Published: April 2014

Abstract
Both the identity and source of the rodent collagenase(s) that mediates matrix remodeling in liver fibrosis remain elusive. We have recently demonstrated an unequivocal role for scar-associated macrophages (SAMs) in the spontaneous resolution of liver fibrosis and sought to determine whether SAMs are the source of matrix metalloproteinase (MMP) 13 (collagenase 3), considered to be the primary interstitial collagenase in rodents. In this study, we demonstrate an association between MMP13 expression and the presence of SAMs in the regression of experimental liver fibrosis. mmp13 gene expression was restricted to regions of fibrosis that were rich in SAMs. Both MMP13 mRNA and protein colocalized to large phagocytes within and directly apposed to hepatic scars. Using the CD11b-DTR-transgenic mouse to deplete SAMs in a model of chronic CCl4 injury, we found that SAM depletion resulted in a 5-fold reduction in mmp13 message (p = 0.005). Furthermore, resolution of CCl4-induced fibrosis was retarded in MMP13-deficient mice. Thus, SAMs selectively, during resolution of fibrosis induce and use the major collagenase MMP13 to mediate the resorption of interstitial matrix and successfully remodel the fibrotic liver.
Some Plasmin-Induced Antibodies Bind to Cardiolipin, Display Lupus Anticoagulant Activity and Induce Fetal Loss in Mice
Authors: Chen Xiao-Xiang , Gu Yue-Ying , Li Shu-Jie , Qian Jie , Hwang Kwan-Ki , Chen Pojen P. , Chen Shun-Le , Yang Cheng-De 
Published: April 2014

Abstract
The combined presence of anti-phospholipid Ab (aPL), thrombosis, and/or fetal loss is recognized as the antiphospholipid syndrome (APS). aPL include anti-cardiolipin Ab (aCL) and/or lupus anticoagulants (LAC, detected as Ig that prolong certain in vitro phospholipid (PL)-restricted blood clotting tests); both aCL and LAC are the diagnostic Ab for APS. Studies show that aPL represent a heterogeneous group of Ab, which recognize various PL, PL-binding plasma proteins, and/or PL-protein complexes. Recently, we found that five of seven patient-derived IgG monoclonal aCL react with thrombin, activated protein C, and plasmin. All three proteins are trypsin-like serine proteases (SP), and are highly homologous in their catalytic domains. Importantly, among these SP autoantigens, the reactive aCL bind to plasmin with the highest affinity, suggesting that plasmin may serve as a major driving autoantigen for some aCL in ∼30% of APS patients who are positive for IgG anti-plasmin Ab. To test this hypothesis, we immunized BALB/c mice with human plasmin and analyzed immune sera for aCL activity and reactivity with relevant SP. We found that some immune sera displayed aCL activity and/or bound to test SP. Subsequently, eight mAb were obtained and studied. The results revealed that one mAb displayed the aCL and the LAC activities and induced fetal loss when injected into pregnant mice. Immunohistological analyses of placentas revealed extensive deposits of activated C3 components. Combined, these data demonstrate that plasmin may serve as a driving Ag for some pathogenic aPL.
Unequal Contribution of Akt Isoforms in the Double-Negative to Double-Positive Thymocyte Transition
Authors: Mao Changchuin , Tili Esmerina G. , Dose Marei , Haks Mariëlle C. , Bear Susan E. , Maroulakou Ioanna , Horie Kyoji , Gaitanaris George A. , Fidanza Vincenzo , Ludwig Thomas , Wiest David L. , Gounari Fotini , Tsichlis Philip N. 
Published: April 2014

Abstract
Pre-TCR signals regulate the transition of the double-negative (DN) 3 thymocytes to the DN4, and subsequently to the double-positive (DP) stage. In this study, we show that pre-TCR signals activate Akt and that pharmacological inhibition of the PI3K/Akt pathway, or combined ablation of Akt1 and Akt2, and to a lesser extent Akt1 and Akt3, interfere with the differentiation of DN3 and the accumulation of DP thymocytes. Combined ablation of Akt1 and Akt2 inhibits the proliferation of DN4 cells, while combined ablation of all Akt isoforms also inhibits the survival of all the DN thymocytes. Finally, the combined ablation of Akt1 and Akt2 inhibits the survival of DP thymocytes. Constitutively active Lck-Akt1 transgenes had the opposite effects. We conclude that, following their activation by pre-TCR signals, Akt1, Akt2, and, to a lesser extent, Akt3 promote the transition of DN thymocytes to the DP stage, in part by enhancing the proliferation and survival of cells undergoing β-selection. Akt1 and Akt2 also contribute to the differentiation process by promoting the survival of the DP thymocytes.
CD83 Knockdown in Monocyte-Derived Dendritic Cells by Small Interfering RNA Leads to a Diminished T Cell Stimulation
Authors: Prechtel Alexander T. , Turza Nadine M. , Theodoridis Alexandros A. , Steinkasserer Alexander 
Published: April 2014

Abstract
Mature human dendritic cells (mDCs) are the most powerful APCs known today, having the unique ability to induce primary immune responses. One of the best known surface markers for mDCs is the glycoprotein CD83, which is strongly up-regulated during maturation, together with costimulatory molecules such as CD80 and CD86. When CD83 surface expression was inhibited by interference with the messenger RNA export or by infection with certain viruses, DCs showed a dramatically reduced capability to induce T cell proliferation. However, in these cases side effects on other cellular functions cannot be excluded completely. In this study we present an efficient method to specifically influence CD83 surface expression by the use of RNA interference. We used small-interfering RNA targeted against CD83 and carefully evaluated an electroporation protocol for the delivery of the duplex into the cells. Furthermore, we identified freshly prepared immature DCs as the best target for the application of a CD83 knockdown and we were also able to achieve a long lasting silencing effect for this molecule. Finally, we were able to confirm that CD83 functions as an enhancer during the stimulation of T cells, significantly increases DC-mediated T cell proliferation, and goes hand in hand with clear changes in cytokine expression during T cell priming. These results were obtained for the first time without the use of agents that might cause unwanted side effects, such as low m.w. inhibitors or viruses. Therefore, this method presents a suitable way to influence DC biology.
Down-Regulation of IL-7Rα Expression in Human T Cells via DNA Methylation
Authors: Kim Hang-Rae , Hwang Kyung-A , Kim Ki-Chan , Kang Insoo 
Published: April 2014

Abstract
IL-7 is critical for the development and survival of T cells. Recently, we found two subsets of human CD8+ T cells expressing IL-7Rαhigh and IL-7Rαlow with different cell survival responses to IL-7. Although these CD8+ T cell subsets have differential IL-7Rα gene expression, the mechanism for this is unknown. DNA methylation is an important gene regulatory mechanism and is associated with the inactivation of gene expression. Thus, we investigated a role for DNA methylation in differentially regulating IL-7Rα gene expression in human CD8+ T cells and Jurkat T cells. IL-7RαhighCD8+ T cells had decreased methylation in the IL-7Rα gene promoter compared with IL-7RαlowCD8+ T cells and Jurkat T cells with low levels of IL-7Rα. Treating Jurkat T cells with 5-aza-2′-deoxycytidine, which reduced DNA methylation, increased IL-7Rα expression. Plus, the unmethylated IL-7Rα gene promoter construct had higher levels of promoter activity than the methylated one as measured by a luciferase reporter assay. These findings suggest that DNA methylation is involved in regulating IL-7Rα expression in T cells via affecting IL-7Rα gene promoter activity, and that the methylation of this gene promoter could be a potential target for modifying IL-7-mediated T cell development and survival.